Rabbit Anti-Human IRS1 (Phospho-Ser1101) polyclonal antibody

Background: Aging is characterized by loss of function of the adaptive immune system, but the underlying causes are poorly understood. To assess the molecular effects of aging on B cell development, we profiled gene expression and chromatin features genome-wide, including histone modifications and chromosome conformation, in bone marrow pro-B and pre-B cells from young and aged mice. Results: Our analysis reveals that the expression levels of most genes are generally preserved in B cell precursors isolated from aged compared with young mice. Nonetheless, age-specific expression changes are observed at numerous genes, including microRNA encoding genes. Importantly, these changes are underpinned by multi-layered alterations in chromatin structure, including chromatin accessibility, histone modifications, long-range promoter interactions, and nuclear compartmentalization. Previous work has shown that differentiation is linked to changes in promoter-regulatory element interactions. We find that aging in B cell precursors is accompanied by rewiring of such interactions. We identify transcriptional downregulation of components of the insulin-like growth factor signaling pathway, in particular downregulation of Irs1 and upregulation of Let-7 microRNA expression, as a signature of the aged phenotype. These changes in expression are associated with specific alterations in H3K27me3 occupancy, suggesting that Polycomb-mediated repression plays a role in precursor B cell aging. Conclusions: Changes in chromatin and 3D genome organization play an important role in shaping the altered gene expression profile of aged precursor B cells. Components of the insulin-like growth factor signaling pathways are key targets of epigenetic regulation in aging in bone marrow B cell precursors.

Lysosomal degradation of the endoplasmic reticulum (ER) via autophagy (ER-phagy) is emerging as a critical regulator of cell homeostasis and function. The recent identification ofER-phagy receptors has shed light on the molecular mechanisms underlining this process. However, the signaling pathways regulatingER-phagy in response to cellular needs are still largely unknown. We found that the nutrient responsive transcription factorsTFEBandTFE3-master regulators of lysosomal biogenesis and autophagy-controlER-phagy by inducing the expression of theER-phagy receptorFAM134B. TheTFEB/TFE3-FAM134B axis promotesER-phagy activation upon prolonged starvation. In addition, this pathway is activated in chondrocytes byFGFsignaling, a critical regulator of skeletal growth.FGFsignaling inducesJNK-dependent proteasomal degradation of the insulin receptor substrate 1 (IRS1), which in turn inhibits thePI3K-PKB/Akt-mTORC1 pathway and promotesTFEB/TFE3 nuclear translocation and enhancesFAM134B transcription. Notably,FAM134B is required for protein secretion in chondrocytes, and cartilage growth and bone mineralization in medaka fish. This study identifies a new signaling pathway that allowsER-phagy to respond to both metabolic and developmental cues.