Insights Into the FOXE3 Transcriptional Network and Disease Mechanisms From the Investigation of a Regulatory Variant Driving Complex Microphthalmia.

Purpose: FOXE3 encodes a highly conserved, lens-enriched transcription factor essential for eye development. Biallelic mutations in FOXE3 are associated with a spectrum of ocular anomalies, ranging from congenital cataracts to complex microphthalmia (CM), with severity and penetrance correlating with genotype. This study aimed to investigate the regulatory landscape of FOXE3 and its contribution to CM.

Characterization of DNA methylation reader proteins in .

In plants, cytosine DNA methylation (mC) is largely associated with transcriptional repression of transposable elements, but it can also be found in the body of expressed genes, referred to as gene body methylation (gbM). gbM is correlated with ubiquitously expressed genes; however, its function, or absence thereof, is highly debated. The different outputs that mC can have raise questions as to how it is interpreted-or read-differently in these sequence and genomic contexts.

Dissecting the roles of MBD2 isoforms and domains in regulating NuRD complex function during cellular differentiation.

The Nucleosome Remodeling and Deacetylation (NuRD) complex is a crucial regulator of cellular differentiation. Two members of the Methyl-CpG-binding domain (MBD) protein family, MBD2 and MBD3, are known to be integral, but mutually exclusive subunits of the NuRD complex. Several MBD2 and MBD3 isoforms are present in mammalian cells, resulting in distinct MBD-NuRD complexes.

DNA sequence and chromatin modifiers cooperate to confer epigenetic bistability at imprinting control regions.

Genomic imprinting is regulated by parental-specific DNA methylation of imprinting control regions (ICRs). Despite an identical DNA sequence, ICRs can exist in two distinct epigenetic states that are memorized throughout unlimited cell divisions and reset during germline formation. Here, we systematically study the genetic and epigenetic determinants of this epigenetic bistability.

Flanking sequence preference modulates de novo DNA methylation in the mouse genome.

Mammalian de novo DNA methyltransferases (DNMT) are responsible for the establishment of cell-type-specific DNA methylation in healthy and diseased tissues. Through genome-wide analysis of de novo methylation activity in murine stem cells we uncover that DNMT3A prefers to methylate CpGs followed by cytosines or thymines, while DNMT3B predominantly methylates CpGs followed by guanines or adenines. These signatures are further observed at non-CpG sites, resembling methylation context observed in specialised cell types, including neurons and oocytes.

DNA methyltransferases hitchhiking on chromatin.

DNA methylation is an epigenetic modification that plays a central regulatory role in various biological processes. Methyl groups are coupled to cytosines by the family of DNA methyltransferases (DNMTs), where DNMT1 is the main maintenance enzyme and the DNMT3 branch of the family is mostly responsible for de novo methylation. The regulation and function of DNA methylation are dependent on the genomic and chromatin context, such as binding sites for transcription factors or the presence of histone marks.

NuRD-interacting protein ZFP296 regulates genome-wide NuRD localization and differentiation of mouse embryonic stem cells.

The nucleosome remodeling and deacetylase (NuRD) complex plays an important role in gene expression regulation, stem cell self-renewal, and lineage commitment. However, little is known about the dynamics of NuRD during cellular differentiation. Here, we study these dynamics using genome-wide profiling and quantitative interaction proteomics in mouse embryonic stem cells (ESCs) and neural progenitor cells (NPCs).

MTF2 recruits Polycomb Repressive Complex 2 by helical-shape-selective DNA binding.

Polycomb-mediated repression of gene expression is essential for development, with a pivotal role played by trimethylation of histone H3 lysine 27 (H3K27me3), which is deposited by Polycomb Repressive Complex 2 (PRC2). The mechanism by which PRC2 is recruited to target genes has remained largely elusive, particularly in vertebrates. Here we demonstrate that MTF2, one of the three vertebrate homologs of Drosophila melanogaster Polycomblike, is a DNA-binding, methylation-sensitive PRC2 recruiter in mouse embryonic stem cells.

Single-Cell DNA Methylation Profiling: Technologies and Biological Applications.

DNA methylation is an epigenetic modification that plays an important role in gene expression regulation, development, and disease. Recent technological innovations have spurred the development of methods that enable us to study the occurrence and biology of this mark at the single-cell level. Apart from answering fundamental biological questions about heterogeneous systems or rare cell types, low-input methods also bring clinical applications within reach.

ZBTB2 reads unmethylated CpG island promoters and regulates embryonic stem cell differentiation.

Proteins that bind to DNA depending on its methylation status play an important role in methylation-mediated regulation of gene expression. Using a variety of genomics and proteomics approaches, we identify zinc finger and BTB domain-containing protein 2 (ZBTB2) as a reader of unmethylated DNA in mouse embryonic stem cells. ZBTB2 preferentially binds to CpG island promoters, where it acts as a transcriptional activator.

The dynamic interactome and genomic targets of Polycomb complexes during stem-cell differentiation.

Although the core subunits of Polycomb group (PcG) complexes are well characterized, little is known about the dynamics of these protein complexes during cellular differentiation. We used quantitative interaction proteomics and genome-wide profiling to study PcG proteins in mouse embryonic stem cells (ESCs) and neural progenitor cells (NPCs). We found that the stoichiometry and genome-wide binding of PRC1 and PRC2 were highly dynamic during neural differentiation.

In need of good neighbours: transcription factors require local DNA hypomethylation for target binding.

Whether and how DNA methylation influences the binding of transcription factors (TFs) to their corresponding DNA sequence motifs remains largely unresolved. In a recent publication, Schübeler and co‐workers (Domcke , 2015) identify a few methylation‐restricted TFs in mouse embryonic stem cells, including NRF1. The authors show that NRF1 binding to its motif can be outcompeted by DNA methylation, suggesting that methylation‐sensitive TFs rely on neighbouring motifs —bound by pioneer TFs—to ensure local hypomethylation.

Perspective on unraveling the versatility of 'co-repressor' complexes.

A multitude of post-translational modifications take place on histones, one of the best studied being acetylation on lysine residues, which is generally associated with gene activation. During the last decades, several so-called co-repressor protein complexes that carry out the reverse process, histone deacetylation, have been identified and characterized, such as the Sin3, N-CoR/SMRT and NuRD complexes. Although a repressive role for these complexes in regulating gene expression is well established, accumulating evidence also points to a role in gene activation.