Regulation of chromatin architecture by transcription factor binding

Author:

Portillo-Ledesma Stephanie12ORCID,Chung Suckwoo1,Hoffman Jill1,Schlick Tamar1234ORCID

Affiliation:

1. Department of Chemistry, 100 Washington Square East, Silver Building, New York University

2. Simons Center for Computational Physical Chemistry, 24 Waverly Place, Silver Building, New York University

3. Courant Institute of Mathematical Sciences, New York University

4. New York University-East China Normal University Center for Computational Chemistry, New York University Shanghai

Abstract

Transcription factors (TF) bind to chromatin and regulate the expression of genes. The pair Myc:Max binds to E-box regulatory DNA elements throughout the genome to control the transcription of a large group of specific genes. We introduce an implicit modeling protocol for Myc:Max binding to mesoscale chromatin fibers at nucleosome resolution to determine TF effect on chromatin architecture and shed light into its mechanism of gene regulation. We first bind Myc:Max to different chromatin locations and show how it can direct fiber folding and formation of microdomains, and how this depends on the linker DNA length. Second, by simulating increasing concentrations of Myc:Max binding to fibers that differ in the DNA linker length, linker histone density, and acetylation levels, we assess the interplay between Myc:Max and other chromatin internal parameters. Third, we study the mechanism of gene silencing by Myc:Max binding to the Eed gene loci. Overall, our results show how chromatin architecture can be regulated by TF binding. The position of TF binding dictates the formation of microdomains that appear visible only at the ensemble level. At the same time, the level of linker histone and tail acetylation, or different linker DNA lengths, regulates the concentration-dependent effect of TF binding. Furthermore, we show how TF binding can repress gene expression by increasing fiber folding motifs that help compact and occlude the promoter region. Importantly, this effect can be reversed by increasing linker histone density. Overall, these results shed light on the epigenetic control of the genome dictated by TF binding.

Funder

National Institute of General Medical Sciences

National Science Foundation

New York University

Publisher

eLife Sciences Publications, Ltd

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