Agenda  Epigenetics and microRNAs – Update –What’s epigenetics? –Preliminary results.

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Agenda  Epigenetics and microRNAs – Update –What’s epigenetics? –Preliminary results

The two main components of the epigenetic code Nature 441, (11 May 2006)

Epigenetics Histone modification Covalent modifications of histones which are involved in chromatin reorganization and regulation of transcription DNA methylation Addition of methyl groups to cytosine affects mRNA transcription Epigenetic modifications are able to modulate the expression of microRNAs, thus affecting the expression of thousands of miRNA target genes.

Epigenetics Histone modification Covalent modifications of histones which are involved in chromatin reorganization and regulation of transcription DNA methylation Addition of methyl groups to cytosine affects mRNA transcription Promoter microRNA gene microRNA expression is influenced by the presence of epigenetic changes in the promoter region or in the gene body Epigenetic modifications are able to modulate the expression of microRNAs, thus affecting the expression of thousands of miRNA target genes.

Epigenetics Histone modification Covalent modifications of histones which are involved in chromatin reorganization and regulation of transcription DNA methylation Addition of methyl groups to cytosine affects mRNA transcription Promoter microRNA gene microRNA expression is influenced by the presence of epigenetic changes in the promoter region or in the gene body pri-miRNA pre-miRNA mature miRNA Epigenetic modifications are able to modulate the expression of microRNAs, thus affecting the expression of thousands of miRNA target genes.

Epigenetics Histone modification Covalent modifications of histones which are involved in chromatin reorganization and regulation of transcription DNA methylation Addition of methyl groups to cytosine affects mRNA transcription Promoter microRNA gene microRNA expression is influenced by the presence of epigenetic changes in the promoter region or in the gene body pri-miRNA pre-miRNA mature miRNA AAAAAA miRNAs regulate gene expression by targeting mRNA for translational inhibition or direct degradation mRNA miRNA Epigenetic modifications are able to modulate the expression of microRNAs, thus affecting the expression of thousands of miRNA target genes.

Connections between epigenetics and microRNAs during embrionic stem cell differentiation Floris M, Wentzen W, Uva P. – NGS Workshop 6-8 October 2010, Bari While efforts to identify the impact of altered epigenetic profiles of miRNAs in cancer have been undertaken, only a few studies have explored the epigenetic regulation of miRNAs during differentiation.

NGS datasets Generated using Illumina GAII - Dataset [ref] hESC (H1) Fetal fibroblasts (IMR90) DNA methylation [2] H3K9me3 [5] H3K27me3 [5] H3K4me1, H3K4me2, H3K4me3, H3K9ac, H3K18ac, H3K27ac, H3K36me3, H2BK5ac, H4K5ac [5] Analysis in progress mRNA-Seq [2] smRNA-Seq [2]

DNA methylation affects miRNA expression Low methylation (DMC <= 2, n 247) log2(RPKM H1 /RPKM IMR90 ) p<0.001 High methylation (DMC > 2, n 68) Differentially methylated (DM) microRNAs were identified by counting the number of cytosines that are differentially methylated (DMC) between cell lines in a region of 2kb centered on the miRNA. Our results show that the higher level of DNA methylation in gene body is associated with the increase of miRNA expression

Histone marks alter miRNA expression log2(RPKM H1 /RPKM IMR90 ) Expression of miRNAs with different types of histone modifications Histone marks affect the expression of miRNA clusters p<0.001 The expression of several microRNA clusters involved in cellular differentiation/proliferation is controlled at the epigenetic level (left): the mir cluster, which is involved in cellular differentiation, is covered by the repressive H3K27me3 domain in hESC; the mir cluster, which promotes cell cycle progression, is repressed in IMR90 cells by both H3K9me3 and H3K27me3 marks.

Next -Integrate additional histone marks available as raw data (Andrea S.): -mapping of the Illumina reads (sample vs control) -identification of regions enriched in histone marks (activating/repressing gene expression) -comparison between cell lines -describe the role of epigenetic modifications on microRNAs expression Same approach could be applied to the study of human diseases (when genome-wide datasets will be available)