The expression of metazoan replication-dependent histone genes is controlled by NPAT and U7 snRNP. NPAT activates transcription of histone genes during S-phase, whereas U7 snRNP is a multi-subunit endonuclease that cleaves the resultant transcripts at the 3' end, yielding mature histone mRNAs. In cycling cells, NPAT and U7 snRNP with its four unique components, U7 snRNA, Lsm10, Lsm11 and FLASH, are highly enriched in Histone Locus Bodies (HLBs), nuclear condensates formed near histone gene loci. Here, we show that in muscle and neural cells that have ceased to replicate their chromatin and permanently exited the cell cycle, HLBs are dismantled and NPAT, FLASH and Lsm11 are detected in the cytoplasm. This observation suggests that in postmitotic cells, NPAT and U7 snRNP become repurposed for functions unrelated to generating histone mRNAs. We identified a highly conserved region in Lsm11 that engages in various protein-protein interactions and likely acts as a universal platform that controls the assembly, localization and function of Lsm11 complexes, including U7 snRNP, during cell growth and differentiation. Since the assembly of U7 snRNP requires SMN, the protein mutated in spinal muscular atrophy (SMA), our results may provide a new perspective on pathophysiology of this neuromuscular disorder.
Xiao-cui Yang, Anthony Desotell, Agata Malinowska et al.· Biology Open· 0 citations
Skeletal muscle aging is characterized by the deterioration of muscle function, which can lead to negative quality-of-life outcomes including frailty and sarcopenia. While understanding the mechanisms of this process is increasingly important as the global population ages, previous molecular studies of skeletal muscle aging have been limited by statistical power and cell type resolution. In this study, we analyzed single-nucleus gene expression and chromatin accessibility data from 287 human skeletal muscle samples from individuals aged 20-79 years to explore sex- and cell type-specific aging effects. Across 467,126 nuclei from 13 cell types, we identify 384 age-associated genes and 4,061 age-associated chromatin regions. These age-associated molecular features are enriched for functional pathways, including metabolic processes, cell-to-cell communication, and senescence Kyoto Encyclopedia of Genes and Genomes KEGG terms. Age-associated closing chromatin was more common across fiber types and sexes than opening chromatin, and was enriched in active enhancer regions while depleted for active transcription start sites. We observe enrichment for specific transcription factor motifs in closing chromatin, including those of glucocorticoid and androgen receptors, both of which play a key role in the maintenance of healthy skeletal muscle. Together, these findings identify an age-associated regulatory shift, largely invisible in matched transcriptomic data, characterized by closing chromatin which reduces accessibility to hormone receptor binding sites and enhancer regions in the muscle fiber epigenome.
Keagan G. Moo, Peter Orchard, A. Varshney et al.· bioRxiv· 0 citations
