Role Of Histone Modification And Histone Variant In The Transcription Regulation

The transcription regulation in eukaryotes occurs at two levels, one is the transcription factors regulation and another involves chromatin. The first includes transcription factors’roles of transcription initiation, elongation and pausing, while the second is regulated by chromatin remodeling complex that modulate the nucleosome thus affect the accessibility of protein binding to DNA. In addition, transcription factors and transcription apparatus can also recruit hitone-modifying enzymes to modify the nucleosomes to regulate the accessibility, and different histone modifications result in different gene expression activity. The histone components of nucleosome, like the replacement of histone variants can also modulate the accessiblity, and the integration of histone variants in the certain regions of the genome plays an important role in gene regulation. Studies of these complex transcription regulation can help us better understand the mechanism of gene expression. One part of our work is to present one practical method of integrating analysis of allele-specificity of protein-DNA interactions in multiple datasets, by studying different transctiption factors and histone modifications in two homologous chromosomes. Another work is to investigate the regulation mechanism of H2A.Z and H3.3for chromatin higher structure and gene transcription activiey, which offers one molecular mechanism for gene expression.The analysis of allele-specificity based on the sequencing data often has low statistical power and little is known about the synergy of allele-specificity among different proteins. We present one new method iASeq to integrate multiple protein-DNA binding information to infer their allele-specificity. iASeq uses a Beyasian hierarchical mixture model to learn correlation patterns of allele-specificity among multiple proteins. The algorithm can then borrow information across datasets to improve detection of of allelic imbalance of proteins. Application to77ENCODE ChlP-seq samples reprensenting34transcription factors and histone modifications and1genomic DNA sample in GM12878cells, we discovered that different proteins skewed toward the same directions in terms of allele-specificity, and also demonstrated the ability of iASeq to improve allelic inference compared to analyzing each individual dataset separately. This part of work, to a great extent, posses an application and inspiration value in the challenge of today’s high-throughput genomic data blowing while lack of computational method and how to reveal its intrinsic biological meaning.The histone variants H2A.Z and H3.3played contradictory roles in gene regulation. The dynamic molecular mechanism during transcription has not been well defined and it is unclear how they poss unique properties on chromatin’s higher structure.We used the mouse embryonic stem cells, combining with our in-house mESC whole genome open chromatin mapping, to look at how the H2A.Z and H3.3’s distribution on the regulatory element enhancer and promoter on a genome-wide scale, and their consequences on gene expression. Our whole geneme ChIP-seq results showed that comparing with the H2A.Z, H3.3had a higher abundance in the open chromatin regions. Morever, H3.3exhibited higher enrichment in those enhancers that located in the open region, comparing with those located in the relatively condensed chromatin. Our experiments results showed that the highly enriched H3.3in the enhancers evicted during the transcription. Integrating our gene expression, we found H2A.Z highly enriched on the repressive promoters, and they also evicted during the transcription. We proposed a molecular model for H2A.Z and H3.3regulation, which elaborated the histone variants’regulation at the chromatin higher structure level, and had a clear understanding for their dynamic regulation during transcription, thus offered one molecular clue for the histone variants’ transcription regulation.