CTCF delimits a DNA methylation transition at the intergenic region between the embryonic and adult α-globin genes

Transcription-driven establishment of DNA methylation at the PWS/AS imprinted region

MOP1 affects DNA methylation, nucleosome occupancy, histone modifications and chromatin conformation at the b1 allele involved in paramutation

The CTCF Paralog BORIS Contributes to the Ovarian Cancer Transcriptional Program by Relaxing CTCF-mediated 3D Genome Organization

This work shows that the germline-specific CTCFL (BORIS) is aberrantly activated in high-grade serous ovarian carcinoma, where it remodels transcriptional, epigenetic, and three-dimensional genome organization by occupying CTCF-bound chromatin loop anchors and weakening CTCF-mediated chromatin insulation.

Unraveling genomic regulatory complexity by adding chromatin accessibility to the long-read sequencing toolkit 2247245

Fiber-seq simultaneously profiles chromatin accessibility, DNA methylation, protein footprints, and genetic variation on single molecules at near—base-pair resolution, revealing how genetic and epigenetic features interact to regulate gene expression and provides a powerful new framework for dissecting immune cell function and disease mechanisms.

Target-Site Selection by Transcription Factors: Roles of DNA, Chromatin, and Cofactor-Mediated Regulation.

Transcription factors (TFs) are sequence-specific DNA-binding proteins that regulate gene-expression programs and cell fate. The ability of a defined combination of four TFs to reprogram differentiated cells into induced pluripotent stem cells illustrates the powerful role of TFs in determining cellular identity. However, TFs usually recognize short and degenerate DNA motifs of approximately 6-12 base pairs, generating thousands to millions of potential motif matches in mammalian genomes. In living cells, TFs occupy only a restricted subset of these sites, indicating that motif presence alone is insufficient for functional target selection. Several layers of regulation contribute to this selective occupancy, including DNA methylation, nucleosome organization, histone modifications, chromatin remodeling, TF oligomerization, TF availability and localization, and cofactors that regulate DNA-binding domains. This review outlines how DNA/chromatin features and TF-centered mechanisms contribute to target-site selection. The principal aim is to highlight DNA-binding domain-directed cofactor regulation as an underappreciated mechanism that modulates TF-DNA binding and may help explain selective genomic occupancy.

SMCHD1’s DNA binding activity enables its stable retention on chromatin

Chromatin proteins play critical roles in gene regulation, yet frequently we do not fully understand how weak DNA binding affinity of such proteins contributes to their locus-specific actions. Here, we studied SMCHD1, a non-canonical SMC-family protein involved in three-dimensional genome organization and gene repression of the inactive X chromosome and its autosomal targets. We replaced endogenous SMCHD1 with GFP-tagged wild-type or hinge-domain DNA-binding mutant SMCHD1 to define the cellular role of DNA binding. The mutant showed reduced enrichment at the inactive X chromosome in female cells, while retaining stable binding at most autosomal binding sites. Impaired DNA binding weakens SMCHD1-mediated gene repression and chromatin-state regulation, producing hypomorphic effect. Multiple live-cell imaging methods reveal that DNA binding constrains SMCHD1 mobility and supports maintenance, rather than initial recruitment, of chromatin-bound SMCHD1 both during interphase and mitosis. Thus, SMCHD1’s weak and sequence-independent DNA binding is a key determinant of its chromatin residence, localization and function. Our findings provide a framework for understanding SMCHD1 and other chromatin proteins with sequence-independent DNA binding activity.