PLX122926

GSE90958: ncRNA transcription-induced changes in nuclear architecture directs with high precision enhancer-promoter interaction

• Organsim mouse
• Type RNASEQ
• Target gene
• Project ARCHS4

It is now well established that transcriptional enhancers dictate with high precision lineage-specific programs of gene expression. However, it has remained an enigma as to how distally located enhancers, while separated by vast genomic distances, selectively target their cognate promoters. To explore the mechanism that underpins this precision-directed targeting we have examined the nuclear architecture of a super-enhancer that regulates the expression of Bcl11b. Bcl11b is a transcriptional regulator that specifies T cell fate and suppresses T-cell malignancy. We show that in T cell progenitors the Bcl11b super-enhancer is located at the nuclear lamina in a transcriptionally silent environment. We found that during T cell commitment the super-enhancer repositioned from the lamina to the transcriptionally permissive compartment. In search for candidate factors that reposition the super-enhancer we identified ThymoD (Thymocyte-Differentiation Factor). ThymoD expression pattern in T cell progenitors immediately precedes that of Bcl11b. We show that ThymoD transcription is required to activate Bcl11b expression, to promote T cell fate, and to suppress the development of T cell malignancy. We found that ThymoD acts in cis to reposition the Bcl11b super-enhancer from the lamina to the nuclear interior. We demonstrate that ThymoD brings the Bcl11b super-enhancer and promoter into close spatial proximity by modulating CTCF and cohesin occupancy and chromatin folding across the Bcl11b intergenic region. These data reveal how ncRNA transcription modulates nuclear location and chromatin folding permitting distally located enhancers to select with high precision their cognate promoter regions. SOURCE: Kees Murre (murre@biomail.ucsd.edu) - Murre lab UCSD