H3.3 actively marks enhancers and primes gene transcription via opening higher-ordered chromatin.
The histone variants H3.3 and H2A.Z have recently emerged as two of the most important features in transcriptional regulation, the molecular mechanism of which still remains poorly understood. In this study, we investigated the regulation of H3.3 and H2A.Z on chromatin dynamics during transcriptional activation. Our in vitro biophysical and biochemical investigation showed that H2A.Z promoted chromatin compaction and repressed transcriptional activity. Surprisingly, with only four to five amino acid differences from the canonical H3, H3.3 greatly impaired higher-ordered chromatin folding and promoted gene activation, although it has no significant effect on the stability of mononucleosomes. We further demonstrated that H3.3 actively marks enhancers and determines the transcriptional potential of retinoid acid (RA)-regulated genes via creating an open chromatin signature that enables the binding of RAR/RXR. Additionally, the H3.3-dependent recruitment of H2A.Z on promoter regions resulted in compaction of chromatin to poise transcription, while RA induction results in the incorporation of H3.3 on promoter regions to activate transcription via counteracting H2A.Z-mediated chromatin compaction. Our results provide key insights into the mechanism of how histone variants H3.3 and H2A.Z function together to regulate gene transcription via the modulation of chromatin dynamics over the enhancer and promoter regions.
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China;
Ping
P
Chen
Jicheng
J
Zhao
Yan
Y
Wang
Min
M
Wang
Haizhen
H
Long
Dan
D
Liang
Li
L
Huang
Zengqi
Z
Wen
Wei
W
Li
Xia
X
Li
Hongli
H
Feng
Haiyong
H
Zhao
Ping
P
Zhu
Ming
M
Li
Qian-fei
QF
Wang
Guohong
G
Li
D000595:Amino Acid Sequence; D000818:Animals; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D005786:Gene Expression Regulation; D016678:Genome; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D046529:Microscopy, Electron, Transmission; D008969:Molecular Sequence Data; D009707:Nucleosomes / Q000378:metabolism / Q000648:ultrastructure; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D000072516:Retinoic Acid 4-Hydroxylase; D016415:Sequence Alignment; D015533:Transcriptional Activation / Q000235:genetics*
D002843:Chromatin; D006657:Histones; D009707:Nucleosomes; D003577:Cytochrome P-450 Enzyme System; D000072516:Retinoic Acid 4-Hydroxylase
H2A.Z; H3.3; chromatin dynamics; gene transcription; higher-ordered chromatin structure; histone variants