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Here, we have used directed differentiation of human induced pluripotent stem cells into atrial or ventricular cardiomyocytes (CMs) to delineate gene regulatory networks (GRNs) that define each identity. We uncovered accessible chromatin regions, transcription factor motifs and key regulatory nodes specific to, or shared by, both CM types, including the transcription factor TBX5, which is linked to genetic susceptibility of ASDs and AF in humans. Complete TBX5 loss resulted in a near absence of atrial CMs, with a concomitant increase in the abundance of other cell types. Reduced dosage of TBX5 in human atrial CMs caused cellular, electrophysiological and molecular phenotypes consistent with features of atrial CM dysfunction. This included dose-dependent aberrant accessibility of many chromatin regions and perturbation of gene regulatory networks of atrial CM identity. These results suggest that, in addition to stemming from ion channel or extracellular matrix dysfunction, atrial diseases such as ASDs or AF may result from disruptions of atrial CM identity.<\/jats:p>","DOI":"10.1242\/dev.205173","type":"journal-article","created":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T09:09:11Z","timestamp":1765876151000},"source":"Crossref","is-referenced-by-count":5,"title":["Reduced TBX5 dosage undermines developmental control of atrial cardiomyocyte identity in a model of human atrial disease"],"prefix":"10.1242","volume":"153","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1207-1490","authenticated-orcid":false,"given":"Irfan S.","family":"Kathiriya","sequence":"first","affiliation":[{"name":"University of California, San Francisco 1 Department of Anesthesia and Perioperative Care , , CA 94143,","place":["USA"]},{"name":"Gladstone Institutes 2 , San Francisco, CA 94158,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5401-6989","authenticated-orcid":false,"given":"Kavitha S.","family":"Rao","sequence":"additional","affiliation":[{"name":"University of California, San Francisco 1 Department of Anesthesia and Perioperative Care , , CA 94143,","place":["USA"]},{"name":"Gladstone Institutes 2 , San Francisco, CA 94158,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5200-6573","authenticated-orcid":false,"given":"Alexander P.","family":"Clark","sequence":"additional","affiliation":[{"name":"University of Virginia 3 Department of Biomedical Engineering , , Charlottesville, VA 22908,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin M.","family":"Hu","sequence":"additional","affiliation":[{"name":"University of California, San Francisco 1 Department of Anesthesia and Perioperative Care , , CA 94143,","place":["USA"]},{"name":"Gladstone Institutes 2 , San Francisco, CA 94158,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0580-5222","authenticated-orcid":false,"given":"Zoe L.","family":"Grant","sequence":"additional","affiliation":[{"name":"Gladstone Institutes 2 , San Francisco, CA 94158,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan N.","family":"Matthews","sequence":"additional","affiliation":[{"name":"University of California, San Francisco 1 Department of Anesthesia and Perioperative Care , , CA 94143,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-6605-8237","authenticated-orcid":false,"given":"Zhe","family":"Chen","sequence":"additional","affiliation":[{"name":"Gladstone Institutes 2 , San Francisco, CA 94158,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3105-9729","authenticated-orcid":false,"given":"Swetansu K.","family":"Hota","sequence":"additional","affiliation":[{"name":"Gladstone Institutes 2 , San Francisco, CA 94158,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9464-8374","authenticated-orcid":false,"given":"Jeffrey J.","family":"Saucerman","sequence":"additional","affiliation":[{"name":"University of Virginia 3 Department of Biomedical Engineering , , Charlottesville, VA 22908,","place":["USA"]},{"name":"Robert M. Berne Cardiovascular Research Center, University of Virginia 4 , Charlottesville, VA 22908,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0804-7597","authenticated-orcid":false,"given":"Benoit G.","family":"Bruneau","sequence":"additional","affiliation":[{"name":"Gladstone Institutes 2 , San Francisco, CA 94158,","place":["USA"]},{"name":"Roddenberry Center for Stem Cell Biology and Medicine, Gladstone Institutes 5 , San Francisco, CA 94158,","place":["USA"]},{"name":"Cardiovascular Research Institute, University of California, San Francisco 6 , CA 94158,","place":["USA"]},{"name":"University of California, San Francisco 7 Department of Pediatrics , , CA 94158,","place":["USA"]},{"name":"Institute of Human Genetics, University of California, San Francisco 8 , CA 94158,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2026,1,23]]},"reference":[{"key":"2026090107563703400_DEV205173C1","doi-asserted-by":"publisher","first-page":"990","DOI":"10.1128\/MCB.26.3.990-1001.2006","article-title":"TGIF inhibits retinoid signaling","volume":"26","author":"Bartholin","year":"2006","journal-title":"Mol. 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