TY - JOUR
T1 - H1 linker histones silence repetitive elements by promoting both histone H3K9 methylation and chromatin compaction
AU - Healton, Sean E.
AU - Pinto, Hugo D.
AU - Mishra, Laxmi N.
AU - Hamilton, Gregory A.
AU - Hamilton, Gregory A.
AU - Wheat, Justin C.
AU - Swist-Rosowska, Kalina
AU - Shukeir, Nicholas
AU - Dou, Yali
AU - Steidl, Ulrich
AU - Jenuwein, Thomas
AU - Gamble, Matthew J.
AU - Gamble, Matthew J.
AU - Skoultchi, Arthur I.
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank Alexander Emelyanov and Dmitry Fyodorov for assistance with H1 purification; members of the Skoultchi laboratory, Cary Weiss, Charles Query, Robert Coleman and David Shechter for stimulating scientific discussion; Emmanuel Burgos for helpful advice regarding the HMT assays; Boris Bartholdy for guidance in computational approaches; Shirley Lee for providing the MLL1 complex; and the Einstein Flow Cytometry core facility (supported by National Cancer Institute [NCI] Grant P30-CA013330). This work was supported in part by funds from the National Institute of General Medical Sciences (NIGMS) (Grant R01-GM116143, to A.I.S.), the NCI (Grant F30-CA210539 to S.E.H.), and an NIH NIGMS Medical Scientist Training Program training grant (T32GM007288, to S.E.H.).
Publisher Copyright:
© 2020 National Academy of Sciences. All rights reserved.
PY - 2020/6/23
Y1 - 2020/6/23
N2 - Nearly 50% of mouse and human genomes are composed of repetitive sequences. Transcription of these sequences is tightly controlled during development to prevent genomic instability, inappropriate gene activation and other maladaptive processes. Here, we demonstrate an integral role for H1 linker histones in silencing repetitive elements in mouse embryonic stem cells. Strong H1 depletion causes a profound de-repression of several classes of repetitive sequences, including major satellite, LINE-1, and ERV. Activation of repetitive sequence transcription is accompanied by decreased H3K9 trimethylation of repetitive sequence chromatin. H1 linker histones interact directly with Suv39h1, Suv39h2, and SETDB1, the histone methyltransferases responsible for H3K9 trimethylation of chromatin within these regions, and stimulate their activity toward chromatin in vitro. However, we also implicate chromatin compaction mediated by H1 as an additional, dominant repressive mechanism for silencing of repetitive major satellite sequences. Our findings elucidate two distinct, H1-mediated pathways for silencing heterochromatin.
AB - Nearly 50% of mouse and human genomes are composed of repetitive sequences. Transcription of these sequences is tightly controlled during development to prevent genomic instability, inappropriate gene activation and other maladaptive processes. Here, we demonstrate an integral role for H1 linker histones in silencing repetitive elements in mouse embryonic stem cells. Strong H1 depletion causes a profound de-repression of several classes of repetitive sequences, including major satellite, LINE-1, and ERV. Activation of repetitive sequence transcription is accompanied by decreased H3K9 trimethylation of repetitive sequence chromatin. H1 linker histones interact directly with Suv39h1, Suv39h2, and SETDB1, the histone methyltransferases responsible for H3K9 trimethylation of chromatin within these regions, and stimulate their activity toward chromatin in vitro. However, we also implicate chromatin compaction mediated by H1 as an additional, dominant repressive mechanism for silencing of repetitive major satellite sequences. Our findings elucidate two distinct, H1-mediated pathways for silencing heterochromatin.
KW - Chromatin
KW - Epigenetics
KW - Linker histones
KW - Repetitive elements
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U2 - 10.1073/pnas.1920725117
DO - 10.1073/pnas.1920725117
M3 - Article
C2 - 32513732
AN - SCOPUS:85087094384
VL - 117
SP - 14251
EP - 14258
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 25
ER -