YY1 control of mitochondrial‐related genes does not account for regulation of immunoglobulin class switch recombination in mice

Abstract

Immunoglobulin class switch recombination (CSR) occurs in activated B cells with increased mitochondrial mass and membrane potential. Transcription factor Yin Yang 1 (YY1) is critical for CSR and for formation of the DNA loops involved in this process. We therefore sought to determine if YY1 knockout impacts mitochondrial gene expression and mitochondrial function in murine splenic B cells, providing a potential mechanism for regulating CSR. We identified numerous genes in splenic B cells differentially regulated when cells are induced to undergo CSR. YY1 conditional knockout caused differential expression of 1129 genes, with 59 being mitochondrial‐related genes. ChIP‐seq analyses showed YY1 was directly bound to nearly half of these mitochondrial‐related genes. Surprisingly, at the time when YY1 knockout dramatically reduces DNA loop formation and CSR, mitochondrial mass and membrane potential were not significantly impacted, nor was there a significant change in mitochondrial oxygen consumption, extracellular acidification rate, or mitochondrial complex I or IV activities. Our results indicate that YY1 regulates numerous mitochondrial‐related genes in splenic B cells, but this does not account for the impact of YY1 on CSR or long‐distance DNA loop formation.

The dystonia gene THAP1 controls DNA double-strand break repair choice

“…Similarly, conditional knockout of Yy1 in mouse B cells (Yy1 flox/flox TAT-Cre) significantly decreased Shld1 expression (Extended Data Fig. 3e) 51 . Strikingly, when we overlapped genes whose expression were differentially regulated by HCF1, YY1 and THAP1 and that were also direct targets of these transcription factors, only two genes Shld1 and Gm11520 (a putative noncoding RNA of unknown function) showed significant enrichment (Fig.…”

Epstein-Barr virus protein EBNA-LP engages YY1 through leucine-rich motifs to promote naïve B cell transformation

“…YY1 deficient naïve B cells also display reduced proliferation upon stimulation compared to controls [48]. YY1 has also been implicated in transcriptional regulation of genes involved in oxidation phosphorylation in B cells [48, 49, 51], upregulation of which is required to avoid cellular arrest upon EBV infection [8]. As EBV-infected cells undergo B cell activation and differentiation in a manner that mimics the remodeling of antigen-experienced B cells through the germinal center [52, 53], YY1 may therefore be required for survival and effective cellular remodeling during EBV infection and transformation.…”

Redefining Autoimmune Disorders’ Pathoetiology: Implications for Mood and Psychotic Disorders’ Association with Neurodegenerative and Classical Autoimmune Disorders

“…It clearly requires investigation as to the presence and expression of the mitochondrial melatonergic pathway in B-cells. The potential importance of the melatonergic pathway in B-cells is highlighted by the data showing the transcription factor yin yang (YY)1 to be crucial in the regulation of B-cell mitochondria gene expression as well as the immunoglobulin (Ig) class switch recombination (CSR) that occurs in activated B-cells [93]. CSR changes the Ig constant region to produce the best Ig isotype to protect against a given pathogen, such as shifting from isotype IgM to IgD.…”

“…The capacity of the array of endogenous and exogenous AhR ligands to activate the mitochondrial AhR may be a contributory factor to the diverse data arising from investigations of AhR activation, including in the course of autoimmune disorders and aging. This may be especially important in B-cells given their dependence on the transcription factors NF-kB and YY1 that are intimately linked to the upregulation of the mitochondrial melatonergic pathway, with YY1 crucial to CSR in activated B-cells [93].…”