Journal Article

Transcriptionally active HERV-H retrotransposons demarcate topologically associating domains in human pluripotent stem cells

Izpisua Belmonte, Juan Carlos, Preissl, Sebastian, Amaral, Maria Luisa, Ren, Bing, Zhu, Quan, Destici, Eugin, Yu, Leqian, Zhang, Yanxiao, Wu, Jun, Lee, Ah Young, Evans, Sylvia M., Chee, Sora, Farah, Elie N., Ye, Zhen, Huang, Hui, Li, Ting, Qiu, Yunjiang, Ma, Kaiyue, Fang, Rongxin, Grinstein, Jonathan D., Hu, Rong, Chi, Neil C.

2019

Overview

Chromatin architecture has been implicated in cell type-specific gene regulatory programs, yet how chromatin remodels during development remains to be fully elucidated. Here, by interrogating chromatin reorganization during human pluripotent stem cell (hPSC) differentiation, we discover a role for the primate-specific endogenous retrotransposon human endogenous retrovirus subfamily H (HERV-H) in creating topologically associating domains (TADs) in hPSCs. Deleting these HERV-H elements eliminates their corresponding TAD boundaries and reduces the transcription of upstream genes, while de novo insertion of HERV-H elements can introduce new TAD boundaries. The ability of HERV-H to create TAD boundaries depends on high transcription, as transcriptional repression of HERV-H elements prevents the formation of boundaries. This ability is not limited to hPSCs, as these actively transcribed HERV-H elements and their corresponding TAD boundaries also appear in pluripotent stem cells from other hominids but not in more distantly related species lacking HERV-H elements. Overall, our results provide direct evidence for retrotransposons in actively shaping cell type- and species-specific chromatin architecture. Genetic deletion or transcriptional silencing of HERV-H elements in human pluripotent stem cells (hPSCs) eliminates nearby topologically associating domain boundaries, while de novo insertion of HERV-H elements can introduce new ones. Mutations of specific HERV-H elements can impact hPSC differentiation.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/136/532 / 631/208/177 / 631/208/200 / Agriculture / Animal Genetics and Genomics / Animals / Binding sites / Bioinformatics / Biomedical and Life Sciences / Biomedicine / Boundaries / Cancer Research / Cardiomyocytes / Cell Differentiation / Chromatin / Chromatin - genetics / Domains / Endogenous retroviruses / Endogenous Retroviruses - genetics / Evolution / Gene expression / Gene Expression Regulation / Gene Function / Gene silencing / Genetic engineering / Genetic transcription / Genomes / Haplotypes / Human Genetics / Humans / Monkeys & apes / Pluripotency / Pluripotent Stem Cells - cytology / Pluripotent Stem Cells - physiology / Primates / Response Elements / Retroelements - genetics / Stem cell transplantation / Stem cells / Transcription Factors - genetics / Transcription Factors - metabolism / Transcription, Genetic