2. Academic Validation
  3. Super-enhancers conserved within placental mammals maintain stem cell pluripotency

Super-enhancers conserved within placental mammals maintain stem cell pluripotency

  • Proc Natl Acad Sci U S A. 2022 Oct 4;119(40):e2204716119. doi: 10.1073/pnas.2204716119.
Juqing Zhang 1,  Yaqi Zhou 2,  Wei Yue 1,  Zhenshuo Zhu 1,  Xiaolong Wu 1,  Shuai Yu 1,  Qiaoyan Shen 1,  Qin Pan 1,  Wenjing Xu 1,  Rui Zhang 1,  Xiaojie Wu 1,  Xinmei Li 3,  Yayu Li 2,  Yunxiang Li 1,  Yu Wang 3,  Sha Peng 1,  Shiqiang Zhang 1,  Anmin Lei 1,  Xinbao Ding 4,  Fan Yang 1,  Xingqi Chen 5,  Na Li 1,  Mingzhi Liao 2,  Wei Wang 6 7,  Jinlian Hua 1
Affiliations

Affiliations

  • 1 College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering & Technology, Northwest A&F University, Yangling 712100, China.
  • 2 College of Life Sciences, Northwest A&F University, Yangling 712100, China.
  • 3 College of Animal Sciences & Technology, Northwest A&F University, Yangling 712100 China.
  • 4 Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853.
  • 5 Department of Immunology, Genetics and Pathology, Uppsala University, 75108 Uppsala, Sweden.
  • 6 National Institute of Biological Sciences, Beijing, 102206, China.
  • 7 Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, 102206 Beijing, China.
PMID: 36161929 DOI: 10.1073/pnas.2204716119
Abstract

Despite pluripotent stem cells sharing key transcription factors, their maintenance involves distinct genetic inputs. Emerging evidence suggests that super-enhancers (SEs) can function as master regulatory hubs to control cell identity and pluripotency in humans and mice. However, whether pluripotency-associated SEs share an evolutionary origin in mammals remains elusive. Here, we performed comprehensive comparative epigenomic and transcription factor binding analyses among pigs, humans, and mice to identify pluripotency-associated SEs. Like typical enhancers, SEs displayed rapid evolution in mammals. We showed that BRD4 is an essential and conserved activator for mammalian pluripotency-associated SEs. Comparative motif enrichment analysis revealed 30 shared transcription factor binding motifs among the three species. The majority of transcriptional factors that bind to identified motifs are known regulators associated with pluripotency. Further, we discovered three pluripotency-associated SEs (SE-SOX2, SE-PIM1, and SE-FGFR1) that displayed remarkable conservation in placental mammals and were sufficient to drive reporter gene expression in a pluripotency-dependent manner. Disruption of these conserved SEs through the CRISPR-Cas9 approach severely impaired stem cell pluripotency. Our study provides insights into the understanding of conserved regulatory mechanisms underlying the maintenance of pluripotency as well as species-specific modulation of the pluripotency-associated regulatory networks in mammals.

Keywords

BRD4; evolution; pigs; pluripotency; super-enhancer.

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