The transcription factor Hhex cooperates with the corepressor Tle3 to promote memory B cell development.
Brian J LaidlawLihui DuanYing XuSara E VazquezBrian J LaidlawPublished in: Nature immunology (2020)
Memory B cells (MBCs) are essential for long-lived humoral immunity. However, the transcription factors involved in MBC differentiation are poorly defined. Here, using single-cell RNA sequencing analysis, we identified a population of germinal center (GC) B cells in the process of differentiating into MBCs. Using an inducible CRISPR-Cas9 screening approach, we identified the hematopoietically expressed homeobox protein Hhex as a transcription factor regulating MBC differentiation. The corepressor Tle3 was also identified in the screen and was found to interact with Hhex to promote MBC development. Bcl-6 directly repressed Hhex in GC B cells. Reciprocally, Hhex-deficient MBCs exhibited increased Bcl6 expression and reduced expression of the Bcl-6 target gene Bcl2. Overexpression of Bcl-2 was able to rescue MBC differentiation in Hhex-deficient cells. We also identified Ski as an Hhex-induced transcription factor involved in MBC differentiation. These findings establish an important role for Hhex-Tle3 in regulating the transcriptional circuitry governing MBC differentiation.
Keyphrases
- transcription factor
- single cell
- crispr cas
- dna binding
- poor prognosis
- genome wide identification
- immune response
- magnetic resonance imaging
- gene expression
- induced apoptosis
- high throughput
- cell proliferation
- rna seq
- computed tomography
- copy number
- oxidative stress
- mass spectrometry
- signaling pathway
- high resolution
- high glucose
- liquid chromatography
- tandem mass spectrometry
- heat stress