Inflammation is a driving force of hematopoietic stem cells(HSCs)aging,causing irreversible exhaustion of functional HSCs.However,the underlying mechanism of HSCs erosion by inflammatory insult remains poorly understo...Inflammation is a driving force of hematopoietic stem cells(HSCs)aging,causing irreversible exhaustion of functional HSCs.However,the underlying mechanism of HSCs erosion by inflammatory insult remains poorly understood.Here,we find that transient LPS exposure primes aged HSCs to undergo accelerated differentiation at the expense of self-renewal,leading to depletion of HSCs.Meanwhile,the central regulator nuclear factor kappa B(NF-κB)mediating functional impairment by inflammation insult induces differential transcriptional response in aged HSCs compared with young HSCs,with precocious activation of myeloid lineage genes.Altered compartmentalization and chromatin loop formation are associated with aging-related differential transcriptional response in HSCs upon lipopolysaccharide(LPS)stimulation.Mechanistically,enhancer and promoter regions of myeloid lineage genes in aged HSCs are more accessible and display more rapid and prominent CTCF occupancy upon LPS stimulation.Our study provides comprehensive resources for the three-dimensional(3D)genome structure of HSCs and sheds light into the ordered genome organization and the associated transcriptome signature underlying HSCs aging.展开更多
基金supported by the National Natural Science Foundation of China (32122030, 32470845, 32330030, 92168205, 92049304, 82030039, 32341004, 82230047, 32122030, 31721003, 32000562, 32170589, 31970758, 31972882, and 92049112)the Ministry of Science and Technology of China (2024YFA1107000, 2022YFC2702200, 2021YFC2700301, 2021YFA1100103, 2021YFA1100302, 2024YFA098701)+5 种基金the Science and Technology Innovation Action Plan of the Science and Technology Commission of Shanghai Municipality (21JC1405500)the innovation team project of universities in Guangdong province (2023KCXTD004)Shanghai Rising-Star Program (A type) of the Science, Technology Commission of Shanghai Municipality (21QA1409500)the Fundamental Research Funds for the Central Universities (22120240435)the Peak Disciplines (Type Ⅳ) of Institutions of Higher Learning in Shanghaithe Guangdong Basic and Applied Basic Research Foundation (2022A1515011204)
文摘Inflammation is a driving force of hematopoietic stem cells(HSCs)aging,causing irreversible exhaustion of functional HSCs.However,the underlying mechanism of HSCs erosion by inflammatory insult remains poorly understood.Here,we find that transient LPS exposure primes aged HSCs to undergo accelerated differentiation at the expense of self-renewal,leading to depletion of HSCs.Meanwhile,the central regulator nuclear factor kappa B(NF-κB)mediating functional impairment by inflammation insult induces differential transcriptional response in aged HSCs compared with young HSCs,with precocious activation of myeloid lineage genes.Altered compartmentalization and chromatin loop formation are associated with aging-related differential transcriptional response in HSCs upon lipopolysaccharide(LPS)stimulation.Mechanistically,enhancer and promoter regions of myeloid lineage genes in aged HSCs are more accessible and display more rapid and prominent CTCF occupancy upon LPS stimulation.Our study provides comprehensive resources for the three-dimensional(3D)genome structure of HSCs and sheds light into the ordered genome organization and the associated transcriptome signature underlying HSCs aging.
