engleski

Towards a histone code for transcription.

Histones are frequently decorated with covalent modifications, which are tightly linked to gene regulation. These modifications are thought to constitute a “Histone Code”, which is read out by proteins to bring about specific downstream effects, supported by the finding that individual modifications can be associated with transcriptional activation or repression. However, in general very little is known about the relationship between histone modifications and the transcriptional process. Using recently published genome wide localization data of 38 histone modifications and one histone variant measured in human CD4+ T-cells we address two major questions: 1) What is the nature of the relationship between histone modifications and transcription? It is possible that the levels of modifications have to exceed a certain threshold in order to promote or repress transcription, thereby encoding the on/off status of a gene. Alternatively, the levels of modifications could encode the actual level of gene expression. 2) Which histone modifications are involved in distinct steps during the transcription cycle? We derived quantitative models to predict the abundance of transcripts from a small number of modifications and relate them to the transcription cycle. We show that our models faithfully capture the measured expression levels of genes, suggesting that the levels of modifications are quantitatively related to gene expression. Given the good agreement between modeled and measured expression levels, we proceed to analyze these models to infer the relationships between modifications and the steps leading from PIC formation and Pol II recruitment to transcription initiation and transcription elongation. A key finding for our analysis is that RNA Polymerase II (Pol II) is much more abundant in expressed high CpG content promoters (HCPs) than in low CpG content promoters (LCPs). We argue that HCPs are regulated at the transition to elongation, while steps preceding initiation are rate limiting in LCPs. Quantitative models involving H3K4me3 and H3K79me1 are the most predictive of the expression levels in LCPs, while HCPs require H3K27ac and H4K20me1. We propose a preliminary “Histone Code of Transcription”, where H3K4me3 is involved in Pol II recruitment and/or initiation, the combinatorial action of H3K27ac and H4K20me1 leads to the transition to elongation, and finally H3K79me1 and H4K20me1 signal the transition to an elongating Pol II.

histone modifications; regression analysis; transcription

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