Citations 3
Chromatin Assembly Factor 1 (CAF-1) facilitates the establishment of facultative heterochromatin during pluripotency exit
Cheng, Liang , Zhang, Xu , Wang, Yan , Gan, Haiyun , Xu, Xiaowei , Lv, Xiangdong , Que, Jianwen , Ördög, Tamás , Zhang, Zhiguo , Zhang, Zhiguo , Hua, Xu , Que, Jianwen
Nucleic Acids Research | October 2, 2019 | Volume: 47 | Issue: 21 | Pages: 11114-11131
Abstract Establishment and subsequent maintenance of distinct chromatin domains during embryonic stem cell (ESC) differentiation are crucial for lineage specification and cell fate determination. Here we show that the histone chaperone Chromatin Assembly Factor 1 (CAF-1), which is recruited to DNA replication forks through its interaction with proliferating cell nuclear antigen (PCNA) for nucleosome assembly, participates in the establishment of H3K27me3-mediated silencing during differentiation. Deletion of CAF-1 p150 subunit impairs the silencing of many genes including Oct4, Sox2 and Nanog as well as the establishment of H3K27me3 at these gene promoters during ESC differentiation. Mutations of PCNA residues involved in recruiting CAF-1 to the chromatin also result in defects in differentiation in vitro and impair early embryonic development as p150 deletion. Together, these results reveal that the CAF-1-PCNA nucleosome assembly pathway plays an important role in the establishment of H3K27me3-mediated silencing during cell fate determination.
Author response: H3.3K27M mutant proteins reprogram epigenome by sequestering the PRC2 complex to poised enhancers
Dong, Fang , Gan, Haiyun , Cheng, Liang , Zhou, Hui , Lee, Jeong‐Heon , Sarkaria, Jann N. , Daniels, David J. , Zhang, Zhiguo
No container title available | July 5, 2018 | Volume: No volume available | Issue: No issue available | Pages: No page available
H3.3K27M mutant proteins reprogram epigenome by sequestering the PRC2 complex to poised enhancers
Dong, Fang , Gan, Haiyun , Cheng, Liang , Lee, Jeong‐Heon , Zhou, Hui , Zhang, Zhiguo , Fang, Dong , Zhang, Zhiguo , Lee, Jeong-Heon , Sarkaria, Jann N. , Daniels, David J.
eLife | June 22, 2018 | Volume: 7 | Issue: No issue available | Pages: No page available
Expression of histone H3.3K27M mutant proteins in human diffuse intrinsic pontine glioma (DIPG) results in a global reduction of tri-methylation of H3K27 (H3K27me3), and paradoxically, H3K27me3 peaks remain at hundreds of genomic loci, a dichotomous change that lacks mechanistic insights. Here, we show that the PRC2 complex is sequestered at poised enhancers, but not at active promoters with high levels of H3.3K27M proteins, thereby contributing to the global reduction of H3K27me3. Moreover, the levels of H3.3K27M proteins are low at the retained H3K27me3 peaks and consequently having minimal effects on the PRC2 activity at these loci. H3K27me3-mediated silencing at specific tumor suppressor genes, including Wilms Tumor 1, promotes proliferation of DIPG cells. These results support a model in which the PRC2 complex is redistributed to poised enhancers in H3.3K27M mutant cells and contributes to tumorigenesis in part by locally enhancing H3K27me3, and hence silencing of tumor suppressor genes.