Screening of histone modulators small molecule library reveals Kdm5b as a major epigenetic modulator of cell cycle gene expression in cardiomyocytes

Screening of histone modulators small molecule library reveals Kdm5b as a major epigenetic modulator of cell cycle gene expression in cardiomyocytes | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 4 February 2026 V1 Latest version Share on Screening of histone modulators small molecule library reveals Kdm5b as a major epigenetic modulator of cell cycle gene expression in cardiomyocytes Authors : Riham R.E. Abouleisa 0000-0001-8883-068X , Dana Hammouri , Kamal Abou Farraj , Abou Bakr M. Salama , Ahmed Gebreil , Mario D.G. Escobar , Joern Huelsmann , … Show All … , Rebecca Liu , Abhijeet. G. Anoop , Katie Nguyen , Sara Taha , Edie Osuma , Pretty Rose Mathew , Ruchira Sivakumar , Abdul Rahman Alkhatib , Luqman Siddique , Om Kulkarni , Anoushka Krishnan , Isaac B. Hilton , Todd K. Rosengart , and Tamer M. A. Mohamed [email protected] Show Fewer Authors Info & Affiliations https://doi.org/10.22541/au.177023174.46125188/v1 259 views 81 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Background and purpose: Cardiomyocyte (CM) cell cycle exit following neonatal stages positively correlates with epigenetic reprogramming that driving postnatal maturation as defined by increased rigidity of the sarcomere and metabolic reprogramming. However, till date, the epigenetic driver(s) for such process has not been identified. In this study, through a small molecule screening, we defined the histone lysine demethylase, Kdm5b , as a major epigenetic driver that controls the CM cell cycle gene expression in neonatal stage and can be reintroduced in adult CMs to induce cell cycle. Experimental approach and key results: By screening a histone modification small molecule library, we identified AS-8531, a Kdm5b inhibitor , as a potent inhibitor of CM cell cycle. Furthermore, Kdm5b knockdown (KD) using shRNA or CM specific knockout mice in naturally proliferating CMs isolated from postnatal day 1 neonatal mouse hearts (NMCM P1) reduced CM proliferation. While Kdm5b overexpression in adult mouse hearts and human heart slices enhances CM proliferation and augment the induced CM proliferation using other cell cycle factors, indicating that Kdm5b is an epigenetic driver that drive CM genetic program that govern CM cell cycle. Mechanistically, RNAseq and CUT&RUN analyses of Kdm5b KD in NMCM P1 revealed that Kdm5b modulates the expression and the enrichment of H3K4me3 methylation around the regulatory regions of the genes involved in cell cycle. Conclusion: Kdm5b functions as an epigenetic driver that regulates the transcription of key factors controlling CM cell cycle. Overexpression of Kdm5b represents a potential strategy to induce regenerative capacity in adult CMs. Supplementary Material File (figures.pdf) Download 9.39 MB File (manuscript.docx) Download 237.54 KB Information & Authors Information Version history V1 Version 1 04 February 2026 Copyright This work is licensed under a Non Exclusive No Reuse License. Authors Affiliations Riham R.E. Abouleisa 0000-0001-8883-068X Baylor College of Medicine Michael E DeBakey Department of Surgery View all articles by this author Dana Hammouri University of Louisville Department of Medicine View all articles by this author Kamal Abou Farraj Baylor College of Medicine Michael E DeBakey Department of Surgery View all articles by this author Abou Bakr M. Salama Baylor College of Medicine Michael E DeBakey Department of Surgery View all articles by this author Ahmed Gebreil University of Louisville Department of Medicine View all articles by this author Mario D.G. Escobar Baylor College of Medicine Michael E DeBakey Department of Surgery View all articles by this author Joern Huelsmann Baylor College of Medicine Michael E DeBakey Department of Surgery View all articles by this author Rebecca Liu Baylor College of Medicine Michael E DeBakey Department of Surgery View all articles by this author Abhijeet. G. Anoop Baylor College of Medicine Michael E DeBakey Department of Surgery View all articles by this author Katie Nguyen Baylor College of Medicine Michael E DeBakey Department of Surgery View all articles by this author Sara Taha Baylor College of Medicine Michael E DeBakey Department of Surgery View all articles by this author Edie Osuma Baylor College of Medicine Michael E DeBakey Department of Surgery View all articles by this author Pretty Rose Mathew Baylor College of Medicine Michael E DeBakey Department of Surgery View all articles by this author Ruchira Sivakumar Alfaisal University College of Medicine View all articles by this author Abdul Rahman Alkhatib Alfaisal University College of Medicine View all articles by this author Luqman Siddique Alfaisal University College of Medicine View all articles by this author Om Kulkarni Rice University View all articles by this author Anoushka Krishnan Rice University View all articles by this author Isaac B. Hilton Rice University Department of Bioengineering View all articles by this author Todd K. Rosengart Baylor College of Medicine Michael E DeBakey Department of Surgery View all articles by this author Tamer M. A. Mohamed [email protected] Baylor College of Medicine Michael E DeBakey Department of Surgery View all articles by this author Metrics & Citations Metrics Article Usage 259 views 81 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Riham R.E. Abouleisa, Dana Hammouri, Kamal Abou Farraj, et al. Screening of histone modulators small molecule library reveals Kdm5b as a major epigenetic modulator of cell cycle gene expression in cardiomyocytes. Authorea . 04 February 2026. DOI: https://doi.org/10.22541/au.177023174.46125188/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. 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