Genome organization and chromatin analysis identify transcriptional downregulation of insulin-like growth factor signaling as a hallmark of aging in developing B cells.
Genome organization and chromatin analysis identify transcriptional downregulation of insulin-like growth factor signaling as a hallmark of aging in developing B cells.
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DOI：
10.1186/s13059-018-1489-y
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发表时间：
2018-09-05
期刊：
影响因子：
12.3
通讯作者：
Varga-Weisz PD
中科院分区：
文献类型：
--
作者：
Koohy H;Bolland DJ;Matheson LS;Schoenfelder S;Stellato C;Dimond A;Várnai C;Chovanec P;Chessa T;Denizot J;Manzano Garcia R;Wingett SW;Freire-Pritchett P;Nagano T;Hawkins P;Stephens L;Elderkin S;Spivakov M;Fraser P;Corcoran AE;Varga-Weisz PD
衰老的特征是适应性免疫系统功能的丧失，但对根本原因知之甚少。为了评估衰老对B细胞发育的分子效应，我们分析了年轻和老年小鼠骨髓前B和前B细胞的基因表达和全基因组染色质特征，包括组蛋白修饰和染色体构象。我们的分析表明，与年轻小鼠相比，大多数基因的表达水平通常保留在从老年小鼠分离的B细胞前体中。尽管如此，在许多基因中观察到年龄特异性表达变化，包括microRNA编码基因。重要的是，这些变化是由染色质结构的多层改变，包括染色质可及性，组蛋白修饰，远程启动子相互作用和核区室化。以前的工作表明，分化与启动子-调控元件相互作用的变化有关。我们发现B细胞前体的老化伴随着这种相互作用的重新连接。我们确定了胰岛素样生长因子信号通路的转录下调成分，特别是Irs 1的下调和Let-7 microRNA表达的上调，作为老年表型的标志。这些表达变化与H3 K27 me 3占有率的特定改变相关，表明Polycomb介导的抑制在前体B细胞衰老中起作用。染色质和3D基因组组织的变化在形成老化前体B细胞的改变的基因表达谱中起重要作用。胰岛素样生长因子信号通路的组分是骨髓B细胞前体衰老中表观遗传调节的关键靶点。本文的在线版本（10.1186/s13059-018-1489-y）包含补充材料，可供授权用户使用。
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. 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. 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. The online version of this article (10.1186/s13059-018-1489-y) contains supplementary material, which is available to authorized users.
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影响因子：
7.7
作者：
Freire-Pritchett P;Schoenfelder S;Várnai C;Wingett SW;Cairns J;Collier AJ;García-Vílchez R;Furlan-Magaril M;Osborne CS;Fraser P;Rugg-Gunn PJ;Spivakov M
通讯作者：
Spivakov M
影响因子：
82.9
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Farr JN;Xu M;Weivoda MM;Monroe DG;Fraser DG;Onken JL;Negley BA;Sfeir JG;Ogrodnik MB;Hachfeld CM;LeBrasseur NK;Drake MT;Pignolo RJ;Pirtskhalava T;Tchkonia T;Oursler MJ;Kirkland JL;Khosla S
通讯作者：
Khosla S
影响因子：
5.2
作者：
Han J;Zhao F;Zhang J;Zhu H;Ma H;Li X;Peng L;Sun J;Chen Z
通讯作者：
Chen Z
影响因子：
16
作者：
Heinz S;Benner C;Spann N;Bertolino E;Lin YC;Laslo P;Cheng JX;Murre C;Singh H;Glass CK
通讯作者：
Glass CK
影响因子：
29
作者：
Blättler SM;Cunningham JT;Verdeguer F;Chim H;Haas W;Liu H;Romanino K;Rüegg MA;Gygi SP;Shi Y;Puigserver P
通讯作者：
Puigserver P