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Yildirim, Eda

Overview:

1. Epigenetic mechanisms regulated by long ncRNAs: their regulatory roles in gene expression, genome stability and cell fate decisions.
2. Nuclear organization: its role in gene expression and genome function.

Positions:

Assistant Professor of Cell Biology

Cell Biology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Affiliate of the Regeneration Next Initiative

Regeneration Next Initiative
School of Medicine

Education:

Ph.D. 2005

Ph.D. — University of California at Los Angeles

News:

Grants:

Training Program in Developmental and Stem Cell Biology

Administered By
Basic Science Departments
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
May 01, 2001
End Date
April 30, 2022

Xist long noncoding RNA mediated gene expression and epigenetic stability in hematologic malignancies

Administered By
Cell Biology
AwardedBy
Leukemia Research Foundation, Inc.
Role
Principal Investigator
Start Date
July 01, 2015
End Date
December 31, 2016

Awards:

Whitehead Scholar Award. Duke University.

Type
University
Awarded By
Duke University
Date
January 01, 2014

Publications:

Genome-wide identification of autosomal genes with allelic imbalance of chromatin state

Authors
Savol, AJ; Wang, PI; Jeon, Y; Colognori, D; Yildirim, E; Pinter, SF; Payer, B; Lee, JT; Sadreyev, RI
MLA Citation
Savol, AJ, Wang, PI, Jeon, Y, Colognori, D, Yildirim, E, Pinter, SF, Payer, B, Lee, JT, and Sadreyev, RI. "Genome-wide identification of autosomal genes with allelic imbalance of chromatin state." Ed. BP Chadwick. PLOS ONE 12.8 (August 10, 2017): e0182568-e0182568.
Source
crossref
Published In
PloS one
Volume
12
Issue
8
Publish Date
2017
Start Page
e0182568
End Page
e0182568
DOI
10.1371/journal.pone.0182568

Allelic Imbalance Is a Prevalent and Tissue-Specific Feature of the Mouse Transcriptome.

In mammals, several classes of monoallelic genes have been identified, including those subject to X-chromosome inactivation (XCI), genomic imprinting, and random monoallelic expression (RMAE). However, the extent to which these epigenetic phenomena are influenced by underlying genetic variation is unknown. Here we perform a systematic classification of allelic imbalance in mouse hybrids derived from reciprocal crosses of divergent strains. We observe that deviation from balanced biallelic expression is common, occurring in ∼20% of the mouse transcriptome in a given tissue. Allelic imbalance attributed to genotypic variation is by far the most prevalent class and typically is tissue-specific. However, some genotype-based imbalance is maintained across tissues and is associated with greater genetic variation, especially in 5' and 3' termini of transcripts. We further identify novel random monoallelic and imprinted genes and find that genotype can modify penetrance of parental origin even in the setting of large imprinted regions. Examination of nascent transcripts in single cells from inbred parental strains reveals that genes showing genotype-based imbalance in hybrids can also exhibit monoallelic expression in isogenic backgrounds. This surprising observation may suggest a competition between alleles and/or reflect the combined impact of cis- and trans-acting variation on expression of a given gene. Our findings provide novel insights into gene regulation and may be relevant to human genetic variation and disease.

Authors
Pinter, SF; Colognori, D; Beliveau, BJ; Sadreyev, RI; Payer, B; Yildirim, E; Wu, C-T; Lee, JT
MLA Citation
Pinter, SF, Colognori, D, Beliveau, BJ, Sadreyev, RI, Payer, B, Yildirim, E, Wu, C-T, and Lee, JT. "Allelic Imbalance Is a Prevalent and Tissue-Specific Feature of the Mouse Transcriptome." Genetics 200.2 (June 2015): 537-549.
PMID
25858912
Source
epmc
Published In
Genetics
Volume
200
Issue
2
Publish Date
2015
Start Page
537
End Page
549
DOI
10.1534/genetics.115.176263

Practical murine hematopathology: a comparative review and implications for research.

Hematologic parameters are important markers of disease in human and veterinary medicine. Biomedical research has benefited from mouse models that recapitulate such disease, thus expanding knowledge of pathogenetic mechanisms and investigative therapies that translate across species. Mice in health have many notable hematologic differences from humans and other veterinary species, including smaller erythrocytes, higher percentage of circulating reticulocytes or polychromasia, lower peripheral blood neutrophil and higher peripheral blood and bone marrow lymphocyte percentages, variable leukocyte morphologies, physiologic splenic hematopoiesis and iron storage, and more numerous and shorter-lived erythrocytes and platelets. For accurate and complete hematologic analyses of disease and response to investigative therapeutic interventions, these differences and the unique features of murine hematopathology must be understood. Here we review murine hematology and hematopathology for practical application to translational investigation.

Authors
O'Connell, KE; Mikkola, AM; Stepanek, AM; Vernet, A; Hall, CD; Sun, CC; Yildirim, E; Staropoli, JF; Lee, JT; Brown, DE
MLA Citation
O'Connell, KE, Mikkola, AM, Stepanek, AM, Vernet, A, Hall, CD, Sun, CC, Yildirim, E, Staropoli, JF, Lee, JT, and Brown, DE. "Practical murine hematopathology: a comparative review and implications for research." Comparative Medicine 65.2 (April 2015): 96-113. (Review)
PMID
25926395
Source
epmc
Published In
Comparative medicine
Volume
65
Issue
2
Publish Date
2015
Start Page
96
End Page
113

Bimodal quantitative relationships between histone modifications for X-linked and autosomal loci.

Gene expression is controlled by coordinated action of many epigenetic mechanisms including covalent histone modifications. Although numerous recurrent patterns of colocalized histone modifications have been associated with specific gene expression states, interrelationships between individual modifications are largely unknown. Here, we analyze quantitative relationships between colocalized histone marks during embryonic stem cell (ESC) differentiation and find that, for autosomal genes, these densities follow bimodal patterns. Analysis of repressive H3K27me3 and activating H3K4me3 modifications reveals the expected anticorrelation between them at active promoters but an unexpected positive correlation at inactive promoters. The two trends connect in a region corresponding to bivalent genes. Interestingly, this region is characterized by maximal H3K27 methylation. Resolving gene bivalency during ESC differentiation does not conform to the expected model of two marks as counteracting and competing forces. Although activated genes acquire H3K4me3 and lose H3K27me3, repressed genes lose H3K4me3 without gaining H3K27me3. The behavior of X-linked genes also deviates from expected models. Allele-specific analysis of chromatin modifications during X-chromosome inactivation (XCI) suggests that the silencing machinery focuses on active genes and depletion of H3K4me3 and that H3K27me3 is most significant during establishment of gene silencing. Our analysis reveals nontrivial relationships between H3K4me3 and H3K27me3, reveals unique aspects of gene bivalency, and demonstrates that XCI does not conform neatly to autosomal models.

Authors
Sadreyev, RI; Yildirim, E; Pinter, SF; Lee, JT
MLA Citation
Sadreyev, RI, Yildirim, E, Pinter, SF, and Lee, JT. "Bimodal quantitative relationships between histone modifications for X-linked and autosomal loci." Proceedings of the National Academy of Sciences of the United States of America 110.17 (April 5, 2013): 6949-6954.
PMID
23564346
Source
epmc
Published In
Proceedings of the National Academy of Sciences of USA
Volume
110
Issue
17
Publish Date
2013
Start Page
6949
End Page
6954
DOI
10.1073/pnas.1216449110

Xist RNA is a potent suppressor of hematologic cancer in mice.

X chromosome aneuploidies have long been associated with human cancers, but causality has not been established. In mammals, X chromosome inactivation (XCI) is triggered by Xist RNA to equalize gene expression between the sexes. Here we delete Xist in the blood compartment of mice and demonstrate that mutant females develop a highly aggressive myeloproliferative neoplasm and myelodysplastic syndrome (mixed MPN/MDS) with 100% penetrance. Significant disease components include primary myelofibrosis, leukemia, histiocytic sarcoma, and vasculitis. Xist-deficient hematopoietic stem cells (HSCs) show aberrant maturation and age-dependent loss. Reconstitution experiments indicate that MPN/MDS and myelofibrosis are of hematopoietic rather than stromal origin. We propose that Xist loss results in X reactivation and consequent genome-wide changes that lead to cancer, thereby causally linking the X chromosome to cancer in mice. Thus, Xist RNA not only is required to maintain XCI but also suppresses cancer in vivo.

Authors
Yildirim, E; Kirby, JE; Brown, DE; Mercier, FE; Sadreyev, RI; Scadden, DT; Lee, JT
MLA Citation
Yildirim, E, Kirby, JE, Brown, DE, Mercier, FE, Sadreyev, RI, Scadden, DT, and Lee, JT. "Xist RNA is a potent suppressor of hematologic cancer in mice." Cell 152.4 (February 2013): 727-742.
PMID
23415223
Source
epmc
Published In
Cell
Volume
152
Issue
4
Publish Date
2013
Start Page
727
End Page
742
DOI
10.1016/j.cell.2013.01.034

Spreading of X chromosome inactivation via a hierarchy of defined Polycomb stations.

X chromosome inactivation (XCI) achieves dosage balance in mammals by repressing one of two X chromosomes in females. During XCI, the long noncoding Xist RNA and Polycomb proteins spread along the inactive X (Xi) to initiate chromosome-wide silencing. Although inactivation is known to commence at the X-inactivation center (Xic), how it propagates remains unknown. Here, we examine allele-specific binding of Polycomb repressive complex 2 (PRC2) and chromatin composition during XCI and generate a chromosome-wide profile of Xi and Xa (active X) at nucleosome-resolution. Initially, Polycomb proteins are localized to ∼150 strong sites along the X and concentrated predominantly within bivalent domains coinciding with CpG islands ("canonical sites"). As XCI proceeds, ∼4000 noncanonical sites are recruited, most of which are intergenic, nonbivalent, and lack CpG islands. Polycomb sites are depleted of LINE repeats but enriched for SINEs and simple repeats. Noncanonical sites cluster around the ∼150 strong sites, and their H3K27me3 levels reflect a graded concentration originating from strong sites. This suggests that PRC2 and H3K27 methylation spread along a gradient unique to XCI. We propose that XCI is governed by a hierarchy of defined Polycomb stations that spread H3K27 methylation in cis.

Authors
Pinter, SF; Sadreyev, RI; Yildirim, E; Jeon, Y; Ohsumi, TK; Borowsky, M; Lee, JT
MLA Citation
Pinter, SF, Sadreyev, RI, Yildirim, E, Jeon, Y, Ohsumi, TK, Borowsky, M, and Lee, JT. "Spreading of X chromosome inactivation via a hierarchy of defined Polycomb stations." Genome research 22.10 (October 2012): 1864-1876.
PMID
22948768
Source
epmc
Published In
Genome research
Volume
22
Issue
10
Publish Date
2012
Start Page
1864
End Page
1876
DOI
10.1101/gr.133751.111

Severely blunted allergen-induced pulmonary Th2 cell response and lung hyperresponsiveness in type 1 transient receptor potential channel-deficient mice.

Transient receptor potential channels (TRPCs) are widely expressed and regulate Ca²⁺ entry in the cells that participate in the pathophysiology of airway hyperreactivity, inflammation, and remodeling. In vitro studies point to a role for TRPC1-mediated Ca²⁺ signaling in several of these cell types; however, physiological evidence is lacking. Here we identify TRPC1 signaling as proinflammatory and a regulator of lung hyperresponsiveness during allergen-induced pulmonary response. TRPC1-deficient (Trpc1(-/-)) mice are hyposensitive to methacholine challenge and have significantly reduced allergen-induced pulmonary leukocyte infiltration coupled with an attenuated T helper type 2 (Th2) cell response. Upon in vitro allergen exposure, Trpc1(-/-) splenocytes show impaired proliferation and T cell receptor-induced IL-2 production. A high number of germinal centers in spleens of Trpc1(-/-) mice and elevated levels of immunoglobulins in their serum are indicative of dysregulated B cell function and homeostasis. Thus we propose that TRPC1 signaling is necessary in lymphocyte biology and in regulation of allergen-induced lung hyperresponsiveness, making TRPC1 a potential target for treatment of immune diseases and asthma.

Authors
Yildirim, E; Carey, MA; Card, JW; Dietrich, A; Flake, GP; Zhang, Y; Bradbury, JA; Rebolloso, Y; Germolec, DR; Morgan, DL; Zeldin, DC; Birnbaumer, L
MLA Citation
Yildirim, E, Carey, MA, Card, JW, Dietrich, A, Flake, GP, Zhang, Y, Bradbury, JA, Rebolloso, Y, Germolec, DR, Morgan, DL, Zeldin, DC, and Birnbaumer, L. "Severely blunted allergen-induced pulmonary Th2 cell response and lung hyperresponsiveness in type 1 transient receptor potential channel-deficient mice." American journal of physiology. Lung cellular and molecular physiology 303.6 (September 2012): L539-L549.
PMID
22797250
Source
epmc
Published In
American journal of physiology. Lung cellular and molecular physiology
Volume
303
Issue
6
Publish Date
2012
Start Page
L539
End Page
L549
DOI
10.1152/ajplung.00389.2011

X-chromosome hyperactivation in mammals via nonlinear relationships between chromatin states and transcription.

Dosage compensation in mammals occurs at two levels. In addition to balancing X-chromosome dosage between males and females via X inactivation, mammals also balance dosage of Xs and autosomes. It has been proposed that X-autosome equalization occurs by upregulation of Xa (active X). To investigate mechanism, we perform allele-specific ChIP-seq for chromatin epitopes and analyze RNA-seq data. The hypertranscribed Xa demonstrates enrichment of active chromatin marks relative to autosomes. We derive predictive models for relationships among Pol II occupancy, active mark densities and gene expression, and we suggest that Xa upregulation involves increased transcription initiation and elongation. Enrichment of active marks on Xa does not scale proportionally with transcription output, a disparity explained by nonlinear quantitative dependencies among active histone marks, Pol II occupancy and transcription. Notably, the trend of nonlinear upregulation also occurs on autosomes. Thus, Xa upregulation involves combined increases of active histone marks and Pol II occupancy, without invoking X-specific dependencies between chromatin states and transcription.

Authors
Yildirim, E; Sadreyev, RI; Pinter, SF; Lee, JT
MLA Citation
Yildirim, E, Sadreyev, RI, Pinter, SF, and Lee, JT. "X-chromosome hyperactivation in mammals via nonlinear relationships between chromatin states and transcription." Nature structural & molecular biology 19.1 (December 4, 2011): 56-61.
PMID
22139016
Source
epmc
Published In
Nature Structural & Molecular Biology
Volume
19
Issue
1
Publish Date
2011
Start Page
56
End Page
61
DOI
10.1038/nsmb.2195

Attenuation of store-operated Ca2+ current impairs salivary gland fluid secretion in TRPC1(-/-) mice.

Agonist-induced Ca(2+) entry via store-operated Ca(2+) (SOC) channels is suggested to regulate a wide variety of cellular functions, including salivary gland fluid secretion. However, the molecular components of these channels and their physiological function(s) are largely unknown. Here we report that attenuation of SOC current underlies salivary gland dysfunction in mice lacking transient receptor potential 1 (TRPC1). Neurotransmitter-regulated salivary gland fluid secretion in TRPC1-deficient TRPC1(-/-) mice was severely decreased (by 70%). Further, agonist- and thapsigargin-stimulated SOC channel activity was significantly reduced in salivary gland acinar cells isolated from TRPC1(-/-) mice. Deletion of TRPC1 also eliminated sustained Ca(2+)-dependent potassium channel activity, which depends on Ca(2+) entry and is required for fluid secretion. Expression of key proteins involved in fluid secretion and Ca(2+) signaling, including STIM1 and other TRPC channels, was not altered. Together, these data demonstrate that reduced SOC entry accounts for the severe loss of salivary gland fluid secretion in TRPC1(-/-) mice. Thus, TRPC1 is a critical component of the SOC channel in salivary gland acinar cells and is essential for neurotransmitter-regulation of fluid secretion.

Authors
Liu, X; Cheng, KT; Bandyopadhyay, BC; Pani, B; Dietrich, A; Paria, BC; Swaim, WD; Beech, D; Yildrim, E; Singh, BB; Birnbaumer, L; Ambudkar, IS
MLA Citation
Liu, X, Cheng, KT, Bandyopadhyay, BC, Pani, B, Dietrich, A, Paria, BC, Swaim, WD, Beech, D, Yildrim, E, Singh, BB, Birnbaumer, L, and Ambudkar, IS. "Attenuation of store-operated Ca2+ current impairs salivary gland fluid secretion in TRPC1(-/-) mice." Proceedings of the National Academy of Sciences of the United States of America 104.44 (October 23, 2007): 17542-17547.
PMID
17956991
Source
epmc
Published In
Proceedings of the National Academy of Sciences of USA
Volume
104
Issue
44
Publish Date
2007
Start Page
17542
End Page
17547
DOI
10.1073/pnas.0701254104

Orai proteins interact with TRPC channels and confer responsiveness to store depletion.

The TRPC (C-type transient receptor potential) class of ion channels has been hypothesized to participate in store-operated Ca(2+) entry (SOCE). Recently, however, STIM1 and Orai1 proteins have been proposed to form SOCE channels. Whether TRPCs participate in SOCE that is dependent on or regulated by Orai has not been explored. Here we show that Orai1 physically interacts with the N and C termini of TRPC3 and TRPC6, and that in cells overexpressing either TRPC3 or TRPC6 in a store-depletion insensitive manner, these TRPCs become sensitive to store depletion upon expression of an exogenous Orai. Thus, Orai-1, -2, and -3 enhanced thapsigargin-induced calcium entry by 50-150% in cells stably overexpressing either TRPC3 or TRPC6. Orai1 expression had no significant effect on endogenous, thapsigargin-induced calcium entry in wild-type cells (HEK-293, COS1), in HEK cells expressing a thapsigargin-sensitive variant of TRPC3 (TRPC3a), or in HEK cells overexpressing another membrane protein, V1aR. Single-channel cation currents present in membrane patches of TRPC3-overexpressing cells were suppressed by expression of Orai1. We propose that Orai proteins by interacting with TRPCs act as regulatory subunits that confer STIM1-mediated store depletion sensitivity to these channels.

Authors
Liao, Y; Erxleben, C; Yildirim, E; Abramowitz, J; Armstrong, DL; Birnbaumer, L
MLA Citation
Liao, Y, Erxleben, C, Yildirim, E, Abramowitz, J, Armstrong, DL, and Birnbaumer, L. "Orai proteins interact with TRPC channels and confer responsiveness to store depletion." Proceedings of the National Academy of Sciences of the United States of America 104.11 (March 7, 2007): 4682-4687.
PMID
17360584
Source
epmc
Published In
Proceedings of the National Academy of Sciences of USA
Volume
104
Issue
11
Publish Date
2007
Start Page
4682
End Page
4687
DOI
10.1073/pnas.0611692104

TRPC2: molecular biology and functional importance.

TRPC (canonical transient receptor potential) channels are the closest mammalian homologs of Drosophila TRP and TRP-like channels. TRPCs are rather nonselective Ca2+ permeable cation channels and affect cell functions through their ability to mediate Ca2+ entry into cells and their action to collapse the plasma membrane potentials. In neurons the latter function leads to action potentials. The mammalian genome codes for seven TRPCs of which TRPC2 is the largest with the most restricted pattern of expression and has several alternatively spliced variants. Expressed in model cells, TRPC2 mediates both receptor- and store depletion-triggered Ca2+ entry. TRPC2 is unique among TRPCs in that its complete gene has been lost from the Old World monkey and human genomes, in which its remnants constitute a pseudogene. Physiological roles for TRPC2 have been studied in mature sperm and the vomeronasal sensory system. In sperm, TRPC2 is activated by the sperm's interaction with the oocyte's zona pellucida, leading to entry of Ca2+ and activation of the acrosome reaction. In the vomeronasal sensory organ (VNO), TRPC2 was found to constitute the transduction channel activated through signaling cascade initiated by the interaction of pheromones with V1R and V2R G protein-coupled receptors on the dendrites of the sensory neurons. V1Rs and V2Rs, the latter working in conjunction with class I MHC molecules, activate G(i)- and G(o)-type G proteins which in turn trigger activation of TRPC2, initiating an axon potential that travels to the axonal terminals. The signal is then projected to the glomeruli of the auxiliary olfactory bulb from where it is carried first to the amygdala and then to higher cortical cognition centers. Immunocytochemistry and gene deletion studies have shown that (1) the V2R-G(o)-MHCIb-beta2m pathway mediates male aggressive behavior in response to pheromones; (2) the V1R-G(i2) pathway mediates mating partner recognition, and (3) these differences have an anatomical correlate in that these functional components are located in anatomically distinct compartments of the VNO. Interestingly, these anatomically segregated signaling pathways use a common transduction channel, TRPC2.

Authors
Yildirim, E; Birnbaumer, L
MLA Citation
Yildirim, E, and Birnbaumer, L. "TRPC2: molecular biology and functional importance." Handbook of experimental pharmacology 179 (January 2007): 53-75. (Review)
PMID
17217050
Source
epmc
Published In
Handbook of experimental pharmacology
Issue
179
Publish Date
2007
Start Page
53
End Page
75

Increased Vascular Smooth Muscle Contractility in TRPC6-/- Mice

Authors
Dietrich, A; Mederos y Schnitzler, M; Gollasch, M; Gross, V; Storch, U; Dubrovska, G; Obst, M; Yildirim, E; Salanova, B; Kalwa, H; Essin, K; Pinkenburg, O; Luft, FC; Gudermann, T; Birnbaumer, L
MLA Citation
Dietrich, A, Mederos y Schnitzler, M, Gollasch, M, Gross, V, Storch, U, Dubrovska, G, Obst, M, Yildirim, E, Salanova, B, Kalwa, H, Essin, K, Pinkenburg, O, Luft, FC, Gudermann, T, and Birnbaumer, L. "Increased Vascular Smooth Muscle Contractility in TRPC6-/- Mice." Molecular and Cellular Biology 25.24 (December 15, 2005): 11191-11191.
Source
crossref
Published In
Molecular and Cellular Biology
Volume
25
Issue
24
Publish Date
2005
Start Page
11191
End Page
11191
DOI
10.1128/MCB.25.24.11191.2005

Increased vascular smooth muscle contractility in TRPC6-/- mice.

Among the TRPC subfamily of TRP (classical transient receptor potential) channels, TRPC3, -6, and -7 are gated by signal transduction pathways that activate C-type phospholipases as well as by direct exposure to diacylglycerols. Since TRPC6 is highly expressed in pulmonary and vascular smooth muscle cells, it represents a likely molecular candidate for receptor-operated cation entry. To define the physiological role of TRPC6, we have developed a TRPC6-deficient mouse model. These mice showed an elevated blood pressure and enhanced agonist-induced contractility of isolated aortic rings as well as cerebral arteries. Smooth muscle cells of TRPC6-deficient mice have higher basal cation entry, increased TRPC-carried cation currents, and more depolarized membrane potentials. This higher basal cation entry, however, was completely abolished by the expression of a TRPC3-specific small interference RNA in primary TRPC6(-)(/)(-) smooth muscle cells. Along these lines, the expression of TRPC3 in wild-type cells resulted in increased basal activity, while TRPC6 expression in TRPC6(-/-) smooth muscle cells reduced basal cation influx. These findings imply that constitutively active TRPC3-type channels, which are up-regulated in TRPC6-deficient smooth muscle cells, are not able to functionally replace TRPC6. Thus, TRPC6 has distinct nonredundant roles in the control of vascular smooth muscle tone.

Authors
Dietrich, A; Mederos Y Schnitzler, M; Gollasch, M; Gross, V; Storch, U; Dubrovska, G; Obst, M; Yildirim, E; Salanova, B; Kalwa, H; Essin, K; Pinkenburg, O; Luft, FC; Gudermann, T; Birnbaumer, L
MLA Citation
Dietrich, A, Mederos Y Schnitzler, M, Gollasch, M, Gross, V, Storch, U, Dubrovska, G, Obst, M, Yildirim, E, Salanova, B, Kalwa, H, Essin, K, Pinkenburg, O, Luft, FC, Gudermann, T, and Birnbaumer, L. "Increased vascular smooth muscle contractility in TRPC6-/- mice." Molecular and cellular biology 25.16 (August 2005): 6980-6989.
PMID
16055711
Source
epmc
Published In
Molecular and Cellular Biology
Volume
25
Issue
16
Publish Date
2005
Start Page
6980
End Page
6989
DOI
10.1128/mcb.25.16.6980-6989.2005

Molecular cloning of TRPC3a, an N-terminally extended, store-operated variant of the human C3 transient receptor potential channel.

AK032317 is the GenBank accession no. of a full-length RIKEN mouse cDNA. It encodes a putative variant of the C3-type TRPC (transient receptor potential channel) that differs from the previously cloned murine TRPC3 cDNA in that it has a 5' extension stemming from inclusion of an additional exon (exon 0). The extended cDNA adds 62 aa to the sequence of the murine TRPC3. Here, we report the cloning of a cDNA encoding the human homologue of this extended TRPC3 having a highly homologous 73-aa N-terminal extension, referred to as hTRPC3a. A query of the GenBank genomic database predicts the existence of a similar gene product also in rats. Transient expression of the longer TRPC3a in human embryonic kidney (HEK) cells showed that it mediates Ca2+ entry in response to stimulation of the Gq-phospholipase C beta pathway, which is similar to that mediated by the shorter hTRPC3. However, after isolation of HEK cells expressing hTRPC3 in stable form, TRPC3a gave rise to Ca2+-entry channels that are not only activated by the Gq-phospholipase C beta pathway (receptor-activated Ca entry) but also by thapsigargin triggered store depletion. In conjunction with findings from our and other laboratories that TRPC1, TRPC2, TRPC4, TRPC5, and TRPC7, can each mediate store-depletion-activated Ca2+ entry in mammalian cells, our findings with hTRC3a support our previous proposal that TRPCs form capacitative Ca-entry channels.

Authors
Yildirim, E; Kawasaki, BT; Birnbaumer, L
MLA Citation
Yildirim, E, Kawasaki, BT, and Birnbaumer, L. "Molecular cloning of TRPC3a, an N-terminally extended, store-operated variant of the human C3 transient receptor potential channel." Proceedings of the National Academy of Sciences of the United States of America 102.9 (March 2005): 3307-3311.
PMID
15728370
Source
epmc
Published In
Proceedings of the National Academy of Sciences of USA
Volume
102
Issue
9
Publish Date
2005
Start Page
3307
End Page
3311
DOI
10.1073/pnas.0409908102

Erratum: Increased vascular smooth muscle contractility in TRPC6 -/- mice (Molecular and Cellular Biology (2005) 25, 16 (6980-6989))

Authors
Dietrich, A; Schnitzler, MMY; Gollasch, M; Gross, V; Storch, U; Dubrovska, G; Obst, M; Yildirim, E; Salanova, B; Kalwa, H; Essin, K; Pinkenburg, O; Luft, FC; Gudermann, T; Birnbaumer, L
MLA Citation
Dietrich, A, Schnitzler, MMY, Gollasch, M, Gross, V, Storch, U, Dubrovska, G, Obst, M, Yildirim, E, Salanova, B, Kalwa, H, Essin, K, Pinkenburg, O, Luft, FC, Gudermann, T, and Birnbaumer, L. "Erratum: Increased vascular smooth muscle contractility in TRPC6 -/- mice (Molecular and Cellular Biology (2005) 25, 16 (6980-6989))." Molecular and Cellular Biology 25.24 (2005): 11191--.
Source
scival
Published In
Molecular and Cellular Biology
Volume
25
Issue
24
Publish Date
2005
Start Page
11191-
DOI
10.1128/MCB.25.24.11191.2005

Erratum to “A comparison of the genes coding for canonical TRP channels and their M, V and P relatives” [Cell Calcium 33 (2003) 419–432]

MLA Citation
"Erratum to “A comparison of the genes coding for canonical TRP channels and their M, V and P relatives” [Cell Calcium 33 (2003) 419–432]." Cell Calcium 34.6 (December 2003): 517-517.
Source
crossref
Published In
Cell Calcium
Volume
34
Issue
6
Publish Date
2003
Start Page
517
End Page
517
DOI
10.1016/S0143-4160(03)00153-2

A comparison of the genes coding for canonical TRP channels and their M, V and P relatives.

The mammalian transient receptor potential (TRP) protein gene family consists of a diverse group of cation channels that currently contain at least 26 members. The physiologic functions of many remain unknown. They are structurally similar to Drosophila TRP and have a wide tissue distribution. In the present report, we compare the chromosomal locations, the gene, and primary structures of each of these 26 human TRP family members. Based on primary amino acid analyses, these channels comprise four different subfamilies: C- (canonical or classical), V- (or vanilloid receptor related), M- (melastatin related), and P (PKD)-type. The highest homology within each subfamily and between subfamilies exists in the predicted ion channel domains. Belonging to a given subfamily, however, does not determine the activating stimuli. This is exemplified by the V- and M-subfamilies, both of which have members that respond to temperature and osmolarity. TRP genes vary in their intron-exon organization, with the greatest diversity in the P subfamily. Chromosomal organization analyses revealed that two TRP members are found as direct repeats; TRPV3 follows TRPV1 and TRPV6 follows TRPV5. Both of these duplications appear to be recent as TRPV1 and V3 are more similar to each other than to other members of the TRPV subfamily. The same holds true for TRPV5 and V6. The article presents complication of comparisons including exon-intron boundaries, the amino acid sequence alignments, and the chromosomal organization of each of the presently known TRP channels.

Authors
Birnbaumer, L; Yildirim, E; Abramowitz, J
MLA Citation
Birnbaumer, L, Yildirim, E, and Abramowitz, J. "A comparison of the genes coding for canonical TRP channels and their M, V and P relatives." Cell calcium 33.5-6 (May 2003): 419-432.
PMID
12765687
Source
epmc
Published In
Cell Calcium
Volume
33
Issue
5-6
Publish Date
2003
Start Page
419
End Page
432
DOI
10.1016/s0143-4160(03)00068-x

The mouse C-type transient receptor potential 2 (TRPC2) channel: alternative splicing and calmodulin binding to its N terminus.

Channels of the C-type transient receptor potential (TRPC) are involved in agonist-stimulated and capacitative calcium entry. There are seven TRPCs, all of which have a Ca(2+)-dependent calmodulin (CaM)-binding domain in their C termini. We now tested binding of CaM to TRPC N termini and show that only that of TRPC2 binds CaM in a Ca(2+)-dependent manner. Four TRPC2 cDNAs have been reported: a (also clone 14), b (also clone 17), alpha, and beta. Sequences responsible for CaM binding in TRPC2 a and b are absent from the alpha and beta isoforms. The alpha and beta cDNAs of TRPC2 were reported as alternative forms, when recloning of TRPC2 a and b proved impossible. Here we analyzed total RNA samples from brain and testis for presence of TRPC2 a and b and describe the splicing patterns responsible for their formation, as well as those leading to the alpha and beta forms of TRPC2. We re-assert existence of RNA encoding the TRPC2 a and b, encoded in 21 exons with an initiator ATG in exon 2 for TRPC2a and in exon 4 for TRCP2b. The analysis of alpha and beta TRPC2 cDNAs indicates that although the TRPC2 beta mRNA may exist, the TRPC2 alpha cDNA is derived from an incompletely processed TRPC2a mRNA: It includes in its presumed 5'-untranslated sequence, 713 nt of TRPC2a cDNA fused to 291 nt of an incompletely excised intron. While encoding an active channel in the mouse, the human TRPC2 appears to be a pseudogene. We searched for the human gene in the data bank and located approximately one-half of it in a chromosomal region syntenic to that of the mouse, with similar intron-exon structure. We conclude that the human TRPC2 gene may never have been an active gene because of incomplete ancestral duplication or, if it was complete at one point, that it became inactive upon loss of chromosomal sequences.

Authors
Yildirim, E; Dietrich, A; Birnbaumer, L
MLA Citation
Yildirim, E, Dietrich, A, and Birnbaumer, L. "The mouse C-type transient receptor potential 2 (TRPC2) channel: alternative splicing and calmodulin binding to its N terminus." Proceedings of the National Academy of Sciences of the United States of America 100.5 (March 2003): 2220-2225.
PMID
12601176
Source
epmc
Published In
Proceedings of the National Academy of Sciences of USA
Volume
100
Issue
5
Publish Date
2003
Start Page
2220
End Page
2225
DOI
10.1073/pnas.0438036100

Erratum: "A comparison of the genes coding for canonical TRP channels and their M, V and P relatives" (Cell Calcium (2003) vol. 33 (419-432))

Authors
Birnbaumer, L; Yildirim, E; Abramowitz, J
MLA Citation
Birnbaumer, L, Yildirim, E, and Abramowitz, J. "Erratum: "A comparison of the genes coding for canonical TRP channels and their M, V and P relatives" (Cell Calcium (2003) vol. 33 (419-432))." Cell Calcium 34.6 (2003): 517--.
Source
scival
Published In
Cell Calcium
Volume
34
Issue
6
Publish Date
2003
Start Page
517-
DOI
10.1016/S0143-4160(03)00153-2
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Research Areas:

  • Bone Marrow
  • Cancer
  • Cell Biology
  • Chromosome abnormalities
  • Chromosomes
  • Epigenetics
  • Gene Expression Regulation
  • Hematopoietic Stem Cells
  • Nuclear Envelope
  • X Chromosome
  • X chromosome--Abnormalities