Transcriptionally active HERV-H retrotransposons demarcate topologically associating domains in human pluripotent stem cells
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 t...
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Published in | Nature genetics Vol. 51; no. 9; pp. 1380 - 1388 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Nature Publishing Group
01.09.2019
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Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 N.C.C. and B.R. designed and supervised the experiments, analysis, and data interpretation. Y.Z. implemented the analysis pipeline and analyzed all sequencing datasets, interpreted the results, designed the experiments for HERV-H functional studies. T.L. generated the CRISPR-Cas9-edited cell lines for HERV-H functional studies, performed differentiation and qPCR of the corresponding cell lines. S.P. performed the Hi-C experiments for all stages of cardiomyocyte differentiation and helped with interpretation of the results. M.A. analyzed the HERV-H knock-in data with help from Y.Q. regarding allelic analysis. J.G. and E.N.F. performed cell culture, differentiation and collected cells for Hi-C, ChIP-seq and RNA-seq assays. E.D. contributed to analysis and interpretation of the ChIP-seq data. R.H. performed the Hi-C experiments for HERV-H knock-out, CRISPRi, HERV-H knock-in and primate iPSC cell lines. ChIP-seq experiments were performed by A.Y.L. (H3K27ac), S.C. (CTCF), Q.Z. and H.H. (SMC3). Y.Q. and R.F. helped with the analysis of Hi-C datasets. K.M. helped with the genome editing experiments. L.Y., J.C.I.B. and J.W. cultured and prepared non-human primate iPSCs for sequencing and interpreted data. Z.Y. performed the RNA-seq experiments. S.M.E. helped with interpretation of the results. Y.Z., T.L., S.P., N.C.C., and B.R. wrote the manuscript with input from all authors. these authors contributed equally Author contributions |
ISSN: | 1061-4036 1546-1718 |
DOI: | 10.1038/s41588-019-0479-7 |