Previously we have studies the contribution of histone modifications and their regulatory enzymes to transcriptional regulation in a variety of cellular systems. Our latest efforts have focused on the novel function of DNA methylation in the mammalian genomes. Although the function of DNA methylation in gene promoter regions is well established in transcriptional repression, the function of the evolutionarily conserved widespread distribution of DNA methylation in gene body regions remains incompletely understood. Here, we show that DNA methylation is enriched in included alternatively spliced exons (ASEs) and inhibiting DNA methylation results in aberrant splicing of ASEs. The methyl-CpG binding protein MeCP2 is enriched in included ASEs, particularly those that are also highly DNA methylated, and inhibition of DNA methylation disrupts specific targeting of MeCP2 to exons. Interestingly, ablation of MeCP2 results in increased nucleosome acetylation and aberrant skipping events of ASEs. We further show that inhibition of histone deacetylases leads to a highly significant overlap of exon skipping events caused by knocking-down MeCP2. Together, our data indicate that intragenic DNA methylation operates in exon definition to modulate alternative splicing and can enhance exon recognition via recruitment of the multifunctional protein MeCP2, which thereby maintains local histone hypoacetylation through its established interaction with HDACs.

Project Start
Project End
Budget Start
Budget End
Support Year
11
Fiscal Year
2013
Total Cost
$1,453,527
Indirect Cost
Name
National Heart, Lung, and Blood Institute
Department
Type
DUNS #
City
State
Country
Zip Code
Baranello, Laura; Wojtowicz, Damian; Cui, Kairong et al. (2016) RNA Polymerase II Regulates Topoisomerase 1 Activity to Favor Efficient Transcription. Cell 165:357-71
Wang, Rui-Hong; Zhao, Tingrui; Cui, Kairong et al. (2016) Negative reciprocal regulation between Sirt1 and Per2 modulates the circadian clock and aging. Sci Rep 6:28633
He, Yanghua; Ding, Yi; Zhan, Fei et al. (2016) Corrigendum: The conservation and signatures of lincRNAs in Marek's disease of chicken. Sci Rep 6:19422
Kraushaar, Daniel C; Jin, Wenfei; Maunakea, Alika et al. (2016) Erratum to: Genome-wide incorporation dynamics reveal distinct categories of turnover for the histone variant H3.3. Genome Biol 17:21
Lu, Falong; Liu, Yuting; Inoue, Azusa et al. (2016) Establishing Chromatin Regulatory Landscape during Mouse Preimplantation Development. Cell 165:1375-88
He, Yanghua; Ding, Yi; Zhan, Fei et al. (2015) The conservation and signatures of lincRNAs in Marek's disease of chicken. Sci Rep 5:15184
Krupovic, Mart; Zhi, Ning; Li, Jungang et al. (2015) Multiple layers of chimerism in a single-stranded DNA virus discovered by deep sequencing. Genome Biol Evol 7:993-1001
Mitra, Apratim; Luo, Juan; He, Yanghua et al. (2015) Histone modifications induced by MDV infection at early cytolytic and latency phases. BMC Genomics 16:311
Zhao, Chunping; Carrillo, José A; Tian, Fei et al. (2015) Genome-Wide H3K4me3 Analysis in Angus Cattle with Divergent Tenderness. PLoS One 10:e0115358
Carrillo, José A; He, Yanghua; Luo, Juan et al. (2015) Methylome Analysis in Chickens Immunized with Infectious Laryngotracheitis Vaccine. PLoS One 10:e0100476

Showing the most recent 10 out of 99 publications