| Autor: |
Ochiai, Kyoko, Shima, Hiroki, Tamahara, Toru, Sugie, Nao, Funayama, Ryo, Nakayama, Keiko, Kurosaki, Tomohiro, Igarashi, Kazuhiko |
| Předmět: |
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| Zdroj: |
EMBO Journal; May2024, Vol. 43 Issue 10, p1947-1964, 18p |
| Abstrakt: |
Transcription factors BACH2 and IRF4 are both essential for antibody class-switch recombination (CSR) in activated B lymphocytes, while they oppositely regulate the differentiation of plasma cells (PCs). Here, we investigated how BACH2 and IRF4 interact during CSR and plasma-cell differentiation. We found that BACH2 organizes heterochromatin formation of target gene loci in mouse splenic B cells, including targets of IRF4 activation such as Aicda, an inducer of CSR, and Prdm1, a master plasma-cell regulator. Release of these gene loci from heterochromatin in response to B-cell receptor stimulation was coupled to AKT-mTOR pathway activation. In Bach2-deficient B cells, PC genes' activation depended on IRF4 protein accumulation, without an increase in Irf4 mRNA. Mechanistically, a PU.1-IRF4 heterodimer in activated B cells promoted BACH2 function by inducing gene expression of Bach2 and Pten, a negative regulator of AKT signaling. Elevated AKT activity in Bach2-deficient B cells resulted in IRF4 protein accumulation. Thus, BACH2 and IRF4 mutually modulate the activity of each other, and BACH2 inhibits PC differentiation by both the repression of PC genes and the restriction of IRF4 protein accumulation. Synopsis: Transcription factors (TFs) BACH2 and IRF4 promote antibody class-switch recombination in activated B cells. This study reveals the functional interaction between these two TFs and how the function of IRF4 differs in the absence of BACH2. In naïve mouse splenic B cells, BACH2 represses target gene loci by heterochromatin formation. Upon B cell activation, IRF4 and partner TF PU.1 promote BACH2 function by binding to their composite element and restricting AKT. AKT promotes IRF4 accumulation, required for IRF4 homodimer binding to target motifs. PU.1-IRF4 function is reduced in Bach2-deficient B cells. IRF4 protein accumulates in a transcript-independent manner in Bach2-deficient B cells. During B cell activation, BACH2 restricts plasma cell differentiation by heterochromatin-mediated transcript inhibition and by preventing IRF4 homodimer accumulation. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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