Population Variation and Genetic Control of Modular Chromatin Architecture in Humans

Area of Science:

• Genomics
• Epigenetics
• Gene Regulation

Background:

• Chromatin state variation at gene regulatory elements is common among individuals.
• The genetic underpinnings of this variability are not well understood.

Purpose of the Study:

• To investigate the genetic basis of chromatin state variation.
• To identify molecular mechanisms driving coordinated chromatin changes.

Main Methods:

• Profiling histone modifications, transcription factors (PU.1), RNA polymerase II, and gene expression.
• Analyzing data from 47 whole-genome sequenced lymphoblastoid cell lines.
• Mapping chromatin quantitative trait loci (cQTLs).

Main Results:

• Distinct cis-regulatory elements show coordinated chromatin variation in variable chromatin modules (VCMs).
• VCMs associate with thousands of genes and cluster within chromosomal contact domains.
• Proximal and distal cQTLs explain much of the observed chromatin variation, mapping to TF-bound regions.

Conclusions:

• Genetic variations perturb cooperative interactions between cis-regulatory elements within genomic domains.
• This leads to local, sequence-independent chromatin variation and impacts gene regulation.