Volume 30 Issue 8, August 2023

Pioneer transcription factors access gene regulatory sites embedded within chromatin. They drive gene expression programs vital for cell fate decisions and cellular reprogramming, but how they engage nucleosomal sites at the molecular level is unclear. New results show that they engage histones and collaborate to overcome the nucleosome barrier.

Inactivation of one of the two female X chromosomes involves condensing it into a repressive subnuclear territory, which is depleted of transcriptional components and undergoes late-stage DNA replication. Two new studies unravel how compartmentalization of the inactive mammalian X chromosome affects transcription and DNA replication.

Unlike autosomal genes, X-linked genes are expressed from only one copy in both male and female mammals. How cells increase X-linked gene expression to match autosomal levels is unclear. New evidence suggests that lower levels of RNA modifications on X chromosome-derived transcripts critically regulate mRNA stability and help to balance X-to-autosome gene expression levels.

By studying the folding of chromosomes relative to nuclear bodies in single-cell models, we reveal specialized subnuclear microenvironments linked to specific gene functions. Our models provide insights into a variety of structural features of the genome and unveil key structure–function correlations.

In this study, the authors show that the splicing order of multi-intron-containing transcripts is predetermined and controlled in part by the spliceosomal U2 snRNA, thus safeguarding splicing fidelity.

Here, the authors show that a single substitution in mouse P1, outside of its arginine core and independently of its charge, suffices to alter sperm chromatin structure and associated developmental outcomes.

Here, the authors show that although transcription is severely diminished in nucleated erythrocytes, it persists at genes involved in promoter-proximal pausing of RNA polymerase II. Erythrocyte nuclei exhibit a reoriented architecture with accessible chromatin at the periphery and retain chromatin organization at minidomains surrounding RNA polymerase II-paused gene promoters.

Here, the authors identify four novel regulators of the 2-cell-like state, and thus totipotency, via unbiased CRISPR knockout screens and Dazl re-expression as a readout. They show that these factors act upstream of DPPA2 and DUX, and independently of p53.

The structure of the assembly-competent 5S RNP was elucidated by cryo-EM. These findings provide molecular insight into how this module incorporates into the nascent pre-60S ribosome and how it can affect the MDM2–p53 pathway in human cells.

Here the authors carry out a systematic de novo protein design exploration of novel αβ-folds predicted under a defined set of rules for β-sheet topology, in an effort to find out the extent to which all possible αβ-folds are already sampled in nature.

Here, the authors combine RNA-immunoprecipitation, single-molecule imaging and proteomics to chart the co-translational assembly pathway of the large general transcription factor TFIID complex from its component building blocks.

By leveraging structural and biochemical methods, the authors show that the interbacterial deaminase toxin DddA, a potential gene-editing tool, uses a tandem displacement mechanism to catalyze cytosine-to-uracil conversion in double-stranded DNA.

Here, the authors show that HDAC1 and HDAC2 genetically interact, with each paralog being synthetically lethal with hemizygous deletion of the other. Mechanistically, HDAC1/2 co-deficiency leads to degradation of the NuRD complex, decreased chromatin accessibility and aberrant enhancer-based interactions.

Here, the authors structurally decipher how Cas12m2 protects against mobile genetic elements by tightly binding invading DNA via a unique arginine-rich cluster and its non-canonical RuvC site.

Here, using structural and biochemical methods, the authors reveal the existence of an intermediate state of the influenza polymerase, which allows it to toggle between the transcribing and replicative states.

Here, using population-based modeling on ensemble Hi-C data, the authors provide an expansive overview of how the genic chromatin microenvironment influences its potential involvement in different functions, such as transcription, DNA replication, and chromatin compartmentalization. Their results unveil a key role of nuclear speckles in genome organization.

Here, the authors show that transcripts arising from the X chromosome are less decorated by m⁶A and are more stable than their autosomal counterparts. Consistently, acute depletion of m⁶A preferentially stabilizes autosomal transcripts and thus results in aberrant dosage compensation.

The authors show that the apparent depletion of RNAPII from the inactive X chromosome territory is not due to a biophysical compartmentalization effect, but rather due to the loss of RNAPII bound fraction on chromatin.

Chromosome-wide late replication is an enigmatic hallmark of the inactive X. Here, the authors combined scRepli-seq and 4C-seq to reveal its layered 3D architecture, which could explain local differences in heterochromatin stability.