Embryonic development is marked by the successive restriction of developmental potential and the specification of embryonic and extraembryonic lineages. Yet, how these lineage decisions are established, and how the epigenome is remodelled to promote and restrict cell fate transitions, remains poorly understood. Here, we demonstrate that SALL2 knockdown in primed human pluripotent stem cells (hPSCs) triggers a trophectoderm (TE)-like phenotype, characterized by palisade-like morphology and the up-regulation of TE-associated genes. Mechanistically, SALL2 physically interacts with the key TE driver TEAD4 and maintains bivalent, repressive chromatin (H3K4me3/H3K27me3) at TE-specific loci. Reduced SALL2 led to enhanced TEAD4 occupancy and disrupted H3K27me3 and increased active chromatin marks at TE genes. Importantly, depletion of TEAD4 abolished the TE-like phenotype induced by SALL2 knockdown, demonstrating that TEAD4 is required for the downstream effects of SALL2 loss. In support of this, blastoid-like aggregates can be generated from primed hPSCs with SALL2 knocked down. Together, our findings identify SALL2 as a key epigenetic barrier that restrains TE lineage commitment by limiting TEAD4-dependent activation of the trophoblast transcriptional program. Key findings SALL2 acts as a molecular barrier to trophectoderm differentiation. SALL2 suppresses the trophectoderm by maintaining bivalent repressive chromatin at TEAD4-bound loci. Blastoid-like structures can be generated from primed-state media when SALL2 was knocked down.
Yu Qiao, Jianfei Xu, Lin Zheng et al.· bioRxiv· 0 citations
Skeletal muscle undergoes a progressive decline in mass and function with aging, a condition that in its extreme form is known as sarcopenia. This is driven by complex cellular and molecular alterations, such as shifts in myonucleus composition, increased fibrosis, and fat or immune cell infiltration. Despite extensive research, effective therapeutic interventions for sarcopenia remain limited. Recent advances in single-cell omics technologies have begun to unravel the cellular and molecular heterogeneity of mouse and human skeletal muscle across the lifespan, identifying age-enriched cell states and dynamic transcriptional changes. However, epigenetic regulation during skeletal muscle aging is less well characterized. To help address this gap, we performed single-nucleus Assay for Transposase-Accessible Chromatin using sequencing (snATAC-seq) on skeletal muscle from young adult and aged male mice, generating chromatin accessibility profiles from over 43,000 nuclei. Among other findings, our analyses reveal an age-enriched pro-atrophy subpopulation of type IIb myonuclei marked by increased chromatin accessibility at the Ampd3 locus. Furthermore, we delineate the epigenetic mechanisms underlying the transition of healthy type IIb myonuclei into Ampd3+ myonuclei, revealing key chromatin remodeling events that drive this phenotypic shift. Moreover, by integrating with an existing single-nucleus RNA sequencing dataset of the same anatomical origin, we identified thousands of cell-type-specific cis-regulatory elements related to aging programs. Within these elements, we observed a broad depletion of binding motifs for transcription factors with roles in cellular identity and muscle regeneration, concomitant with the gain of stress-responsive transcription factors. Our work helps understand the epigenetic events underlying mammalian skeletal muscle aging.
J. An, Guang-Shun Lai, Jing Zuo et al.· The FEBS Journal· 0 citations
A residual population of quiescent Phgdhhigh DTCs that survived initial innate immune clearance and became transiently enriched in micrometastases are identified, providing insights into the development of micrometastasis-targeting regimens.
Yunfan Sun, Y. Zhong, Shang Liu et al.· Science· 0 citations