Table of Contents

In this Outlook, Corbett discusses a study in this issue of Genes & Development by Gabs et al. that shows that competing reactions between the nuclear poly(A) binding protein 2 (NAB2) and the cleavage and polyadenylation complex (CPAC) kinetically control poly(A) tail length. Corbett explores the implications of this "kinetic ruler" model in advancing our understanding of post-transcriptional mRNA processing and gene regulation.

In this Outlook, Birchmeier discusses a study by Nicoletti et al. in this issue of Genes & Development that reports that MYOD unconventionally serves as a transcriptional repressor of nonmyogenic fates. Birchmeier highlights the duality of MYOD function as both an activator and a repressor of gene expression that together modulate the myogenic program during muscle development and regeneration.

In this review, Mishra et al. deconstruct the multifaceted role of vitamin B6 in cancer, functioning in a myriad of signaling and metabolic processes that support oncogenesis. They further contemplate the vitamin B6 pathway as a metabolic vulnerability in cancer cells and discuss emerging pharmacological interventions targeting it in a spatial and temporal context-dependent manner.

In this study, Yu et al. use systematic, targeted H3K4me3 deposition at intergenic cis-regulatory elements to elaborate on the genome-wide effect of H3K4me3 on transcription. The dynamic intergenic deposition of H3K4me3 promotes local transcription at permissive chromatin loci independent of enhancer function or target gene activity, suggesting that maintaining balanced H3K4me3 deposition supports transcriptional stability.

In this study, Nicoletti et al. report that MYOD serves as a transcriptional repressor during fibroblast trans-differentiation into skeletal muscle. Contrary to MYOD-activated gene expression, MYOD interacts with promoters and enhancers of the repressed genes by unconventional binding to non-E-box motifs, showcasing the genetic context-dependent complexity of MYOD's function during skeletal myogenesis.

In this study, Matias et al. show that the zinc finger protein KMG and its binding partners fine-tune the transcriptional activity of spermatocyte-specific master regulator tMAC. Together, these factors counteract tMAC binding at weak or cryptic promoters and restrict aberrant transcription while permitting robust transcription from highly expressed tMAC/Aly-dependent promoters, reflecting a sophisticated cell type-specific surveillance system that functions during spermatocyte differentiation.

In this study, Yang et al. characterize the cellular diversification and temporal dynamics of cortical radial glia lineage progression. Cortical progenitor trajectories were dictated by chromatin accessibility as well as stage-specific and cell type-specific transcription factor expression, which together control neurogenesis-to-gliogenesis transition in the cortex.

In this study, Deevy et al. characterize EZH2 variants associated with the developmental disorder Weaver syndrome and identify a dominant-negative, non-loss-of-function mechanism at play that interferes with PRC2 activity. Contrary to EZH2 gain-of-function mutations that are associated with growth restriction, these EZH2 variants impair intergenic H3K27 methylation and chromatin compaction and cause selective cPRC1 eviction that together derepresses growth, highlighting the complexity of the Polycomb system in mammalian development.

In this study, Gabs et al. show that poly(A) tail length is dictated by kinetic competition between poly(A) tail elongation mediated by the cleavage and polyadenylation complex and polyadenylation termination directed by the zinc finger poly(A) binding protein NAB2 in Saccharomyces. NAB2 dimerization and multidomain RNA binding are counterbalanced by the autoregulation of NAB2 protein concentration, which together fine-tune mRNA poly(A) tail synthesis and thus mRNA stability.