A SIRT7-dependent acetylation switch regulates early B cell differentiation and lineage commitment through Pax5.

B lymphopoiesis is orchestrated by lineage-specific transcription factors. In B cell progenitors, lineage commitment is mediated by Pax5, which is commonly mutated in B cell acute lymphoblastic leukemia. Despite its essential role in immunity, the mechanisms regulating Pax5 function remain largely unknown.

Carm1-arginine methylation of the transcription factor C/EBPα regulates transdifferentiation velocity.

Here, we describe how the speed of C/EBPα-induced B cell to macrophage transdifferentiation (BMT) can be regulated, using both mouse and human models. The identification of a mutant of C/EBPα (C/EBPα) that greatly accelerates BMT helped to illuminate the mechanism. Thus, incoming C/EBPα binds to PU.

CTCF is dispensable for immune cell transdifferentiation but facilitates an acute inflammatory response.

Three-dimensional organization of the genome is important for transcriptional regulation. In mammals, CTCF and the cohesin complex create submegabase structures with elevated internal chromatin contact frequencies, called topologically associating domains (TADs). Although TADs can contribute to transcriptional regulation, ablation of TAD organization by disrupting CTCF or the cohesin complex causes modest gene expression changes.

Single cell RNA-seq identifies the origins of heterogeneity in efficient cell transdifferentiation and reprogramming.

Forced transcription factor expression can transdifferentiate somatic cells into other specialised cell types or reprogram them into induced pluripotent stem cells (iPSCs) with variable efficiency. To better understand the heterogeneity of these processes, we used single-cell RNA sequencing to follow the transdifferentation of murine pre-B cells into macrophages as well as their reprogramming into iPSCs. Even in these highly efficient systems, there was substantial variation in the speed and path of fate conversion.

Transcription Factors Drive Tet2-Mediated Enhancer Demethylation to Reprogram Cell Fate.

Here, we report DNA methylation and hydroxymethylation dynamics at nucleotide resolution using C/EBPα-enhanced reprogramming of B cells into induced pluripotent cells (iPSCs). We observed successive waves of hydroxymethylation at enhancers, concomitant with a decrease in DNA methylation, suggesting active demethylation. Consistent with this finding, ablation of the DNA demethylase Tet2 almost completely abolishes reprogramming.

Transcription factors orchestrate dynamic interplay between genome topology and gene regulation during cell reprogramming.

Chromosomal architecture is known to influence gene expression, yet its role in controlling cell fate remains poorly understood. Reprogramming of somatic cells into pluripotent stem cells (PSCs) by the transcription factors (TFs) OCT4, SOX2, KLF4 and MYC offers an opportunity to address this question but is severely limited by the low proportion of responding cells. We have recently developed a highly efficient reprogramming protocol that synchronously converts somatic into pluripotent stem cells.

Charting the molecular links between driver and susceptibility genes in colorectal cancer.

Despite significant advances in the identification of specific genes and pathways important in the onset and progression of colorectal cancer (CRC), mechanistic insight into the relationship between driver and susceptibility genes is needed. In this paper, we systematically explore physical interactions between causative and putative CRC susceptibility genes to reveal the molecular mechanisms involved in tumor biology. In total, we identify 622 high-confidence protein-protein interactions between 42 CRC causative and 65 candidate susceptibility genes.

Self-assembly of human latexin into amyloid-like oligomers.

Background: In conformational disorders, it is not evident which amyloid aggregates affect specific molecular mechanisms or cellular pathways, which cause disease because of their quantity and mechanical features and which states in aggregate formation are pathogenic. Due to the increasing consensus that prefibrillar oligomers play a major role in conformational diseases, there is a growing interest in understanding the characteristics of metastable polypeptide associations.

Results: Here, we show that human latexin, a protein that shares the same fold with cystatin C, assembles into stable spherical amyloid-like oligomers that bind thioflavin-T and congo red similarly to common amyloid structures but do not evolve into fibrils.