Heterochromatin Protein 1β (HP1β) has distinct functions and distinct nuclear distribution in pluripotent versus differentiated cells

Background: Pluripotent embryonic stem cells (ESCs) have the unique ability to differentiate into every cell type and to self-renew. These characteristics correlate with a distinct nuclear architecture, epigenetic signatures enriched for active chromatin marks and hyperdynamic binding of structural chromatin proteins. Recently, several chromatin-related proteins have been shown to regulate ESC pluripotency and/or differentiation, yet the role of the major heterochromatin proteins in pluripotency is unknown. Results: Here we identify Heterochromatin Protein 1β (HP1β) as an essential protein for proper differentiation, and, unexpectedly, for the maintenance of pluripotency in ESCs. In pluripotent and differentiated cells HP1β is differentially localized and differentially associated with chromatin. Deletion of HP1β, but not HP1aα, in ESCs provokes a loss of the morphological and proliferative characteristics of embryonic pluripotent cells, reduces expression of pluripotency factors and causes aberrant differentiation. However, in differentiated cells, loss of HP1β has the opposite effect, perturbing maintenance of the differentiation state and facilitating reprogramming to an induced pluripotent state. Microscopy, biochemical fractionation and chromatin immunoprecipitation reveal a diffuse nucleoplasmic distribution, weak association with chromatin and high expression levels for HP1β in ESCs. The minor fraction of HP1β that is chromatin-bound in ESCs is enriched within exons, unlike the situation in differentiated cells, where it binds heterochromatic satellite repeats and chromocenters. Conclusions: We demonstrate an unexpected duality in the role of HP1β: it is essential in ESCs for maintaining pluripotency, while it is required for proper differentiation in differentiated cells. Thus, HP1β function both depends on, and regulates, the pluripotent state

Differential DNA methylation of vocal and facial anatomy genes in modern humans

Changes in potential regulatory elements are thought to be key drivers of phenotypic divergence. However, identifying changes to regulatory elements that underlie human-specific traits has proven very challenging. Here, we use 63 reconstructed and experimentally measured DNA methylation maps of ancient and present-day humans, as well as of six chimpanzees, to detect differentially methylated regions that likely emerged in modern humans after the split from Neanderthals and Denisovans. We show that genes associated with face and vocal tract anatomy went through particularly extensive methylation changes. Specifically, we identify widespread hypermethylation in a network of face- and voice-associated genes (SOX9, ACAN, COL2A1, NFIX and XYLT1). We propose that these repression patterns appeared after the split from Neanderthals and Denisovans, and that they might have played a key role in shaping the modern human face and vocal tract.TMB is supported by BFU2017-86471-P (MINECO/FEDER, UE), U01 MH106874 grant, Howard Hughes International Early Career, Obra Social “La Caixa” and Secretaria d’Universitats i Recerca and CERCA Program del Departament d’Economia i Coneixement de la Generalitat de Catalunya. D.R. is an Investigator of the Howard Hughes Medical Institute and is also supported by an Allen Discovery Center for the Study of Human Brain Evolution funded the Paul G. Allen Family Foundation. C.L.-F. is supported by FEDER and BFU2015-64699-P grant from the Spanish government. R.P. was supported by ERC starting grant ADNABIOARC (263441). R.M.G. and J.M.O. are supported by NYSTEM contract C030133. Funding for the collection and processing of the 850K chimpanzee data was provided by the Leakey Foundation Research Grant for Doctoral Students, Wenner-Gren Foundation Dissertation Fieldwork Grant (Gr. 9310), James F. Nacey Fellowship from the Nacey Maggioncalda Foundation, International Primatological Society Research Grant, Sigma Xi Grant-in-Aid of Research, Center for Evolution and Medicine Venture Fund (ASU), Graduate Research and Support Program Grant (GPSA, ASU), and Graduate Student Research Grant (SHESC, ASU) to G.H. Collection of the chimpanzee bone from Tanzania was funded by the Jane Goodall Institute, and grants from the US National Institutes of Health (AI 058715) and National Science Foundation (IOS-1052693), and facilitated by Elizabeth Lonsdorf and Beatrice Hahn