UBR2 mediates transcriptional silencing during spermatogenesis via histone ubiquitination.
Ubiquitination of histones provides an important mechanism regulating chromatin remodeling and gene expression. Recent studies have revealed ubiquitin ligases involved in histone ubiquitination, yet the responsible enzymes and the function of histone ubiquitination in spermatogenesis remain unclear. We have previously shown that mice lacking the ubiquitin ligase UBR2, one of the recognition E3 components of the N-end rule proteolytic pathway, are infertile associated with meiotic arrest at prophase I. We here show that UBR2 localizes to meiotic chromatin regions, including unsynapsed axial elements linked to chromatin inactivation, and mediates transcriptional silencing via the ubiquitination of histone H2A. UBR2 interacts with the ubiquitin conjugating enzyme HR6B and its substrate H2A and promotes the HR6B-H2A interaction and the HR6B-to-H2A transfer of ubiquitin. UBR2 and ubiquitinated H2A (uH2A) spatiotemporally mark meiotic chromatin regions subject to transcriptional silencing, and UBR2-deficient spermatocytes fail to induce the ubiquitination of H2A during meiosis. UBR2-deficient spermatocytes are profoundly impaired in chromosome-wide transcriptional silencing of genes linked to unsynapsed axes of the X and Y chromosomes. Our findings suggest that insufficiency in UBR2-dependent histone ubiquitination triggers a pachytene checkpoint system, providing a new insight into chromatin remodeling and gene expression regulation.
An
Jee Young
JY
Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Center for Pharmacogenetics, Pittsburgh, PA 15261, USA.
Kim
Eun-A
EA
Jiang
Yonghua
Y
Zakrzewska
Adriana
A
Kim
Dong Eun
DE
Lee
Min Jae
MJ
Mook-Jung
Inhee
I
Zhang
Yi
Y
Kwon
Yong Tae
YT
D000818:Animals; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly / Q000235:genetics / Q000502:physiology; D020868:Gene Silencing / Q000502:physiology*; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008297:Male; D008540:Meiosis / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D013090:Spermatocytes / Q000378:metabolism; D013091:Spermatogenesis / Q000235:genetics* / Q000502:physiology*; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D014960:X Chromosome / Q000235:genetics / Q000378:metabolism; D014998:Y Chromosome / Q000235:genetics / Q000378:metabolism
D002843:Chromatin; D006657:Histones; C465394:Ube2b protein, mouse; D044763:Ubiquitin-Conjugating Enzymes; C511160:UBR2 protein, mouse; D044767:Ubiquitin-Protein Ligases