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 FY22 we accomplished the following: The first phase of a study of the effects of age on B cell development was completed. We found large scale chromosome re-organization in pro-B cells from old mice. The gene encoding Ebf1 was located in a compartment that changed from euchromatin to heterochromatin in old pro-B cells, accompanied by alteration of chromatin loops and reduced gene expression. The consequences of reduced Ebf1 expression were examined in Ebf1+/- (heterozygote) pro-B cells. The topologically associated domain (TAD) containing the immunoglobulin heavy chain gene (IgH) locus was negatively affected in old pro-B cells. We propose that the resulting loss of interactions reduce distal VH gene recombination. A manuscript describing these studies is ready for submission. We also 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 hypothesize that this mechanism contributes to hematopoietic skewing towards myelopoiesis in old mice and humans.