Chromosome movements that regulate tissue-specific gene expression

National Institute On Aging

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Abstract

The 3-dimensional chromatin configuration of IgH alleles ensures 1) utilization of a diverse repertoire of variable (VH) gene segments and 2) class switch recombination (CSR) to express different heavy chain isotypes during immune responses. Each of these critical processes is initiated by specialized enzymes that target the IgH locus in the context of this 3D structure. The RAG recombinase operates during B cell development and activation-induced deaminase (AID) initiates CSR. The scaffolding proteins CTCF and YY1 have been implicated in establishing 3D configuration of IgH alleles. During FY23 we accomplished the following: The study describing changes in 3D chromosome structure were completed and submitted for publication. Revisions for this manuscript are ongoing. During follow up experiments we found that the Ebf1 locus , that moves from chromatin compartment A to B during aging, also re-locates closer to the nuclear periphery in progenitor B cells from aged mice. Another key gene involved in B cell development, Foxo1, is also expressed at lower levels in old pro-B cells, but the mechanism involved is distinct from Ebf1 and appears to be re-location closer to gamma satellite positive centromeric heterochromatin. We also mapped genome-wide distributions of chromatin modifying enzymes and remodeling complexes in young and old pro-B cells. The revised manuscript is expected to be re-submitted for consideration in 1-2 months. We had previously largely completed analysis of a parallel epigenetic pathway that negatively impacts B cell development in old mice. This pathway affects facultative heterochromatin formation via polycomb repressive complex (PRC) 2, resulting in aberrant activation of myeloid lineage-specifying genes in old pro-B cells. We hypothesized that this mechanism contributes to hematopoietic skewing towards myelopoiesis in old mice and humans. In further investigating this pathway we found that the inflammatory cytokine milieu of the bone marrow contributes to reduced PRC2 activity in aged pro-B cells.