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 FY25 we accomplished the following: 1)We completed analysis of a second epigenetic pathway that skews hematopoiesis towards myeloid differentiation during aging. The manuscript has ben completed and will be submitted for publication before end of FY25. 2)We completed the first phase of analyses of a study aimed at identifying to what extent the aging bone marrow microenvironment contributes to B cell developmental defects during aging. For this, bone marrow transplants (BMTs) were carried out with young/old stem cells into young/old recipient mice. Single cell RNA-seq studies were carried out with B cell precursors obtained 4 months after BMT. Our results indicate that the aging environment makes a bigger contribution than hematopoietic precursors to aging phenotypes of B cell differentiation. 3) We initiated whole genome methylation analyses of B cell differentiation changes during aging. We purified progenitor (pro-) and precursor (pre-) B cells from bone marrow of young and aged mice and prepared genomic DNA for sodium bisulfite modification and sequencing. Data accumulation is complete, analysis has been initiated.