Biology subjects

Narendra, V.

Publications and source records attributed to Narendra, V..

3 recordsLinked to original sources

bioRxiv2026

Epigenetic Reactivation of Lineage Differentiation to Target Leukemia

Chromatin regulation critically influences gene expression and cancer progression, yet the functions of chromatin adaptors remain incompletely defined. Using focused CRISPR screening, we identified TRIM28, a multi-domain chromatin adaptor, as a dependency in acute leukemia, where its depletion impaired leukemia cell proliferation in vitro and in vivo, while activating neutrophil differentiation programs. Integrative transcriptomic and chromatin profiling revealed that TRIM28 acts as a co-repressor of neutrophil-associated loci independently of H3K9 methylation, and that TRIM28 loss drives terminal differentiation of leukemia cells into functionally mature neutrophil-like cells with reduced leukemic potential. We developed a selective small-molecule TRIM28 inhibitor that binds the TRIM28 PHD-bromodomain, phenocopies TRIM28 loss across biochemical and cellular assays, exhibits low micromolar anti-leukemia activity, induces neutrophil differentiation, and synergizes with Menin inhibition. Together, these findings, spanning target discovery, mechanism of action, and chemical probe development, establish TRIM28 as a regulator of myeloid cell fate and a promising pro-differentiation therapeutic target in acute leukemia.

cancer biology↗

bioRxiv2020

A CRISPR Screen Identifies Myc-associated Zinc Finger Protein (MAZ) as an Insulator Functioning at CTCF boundaries in Hox Clusters

The essential CCCTC-binding factor (CTCF) is critical to three-dimensional (3D) genome organization. CTCF binding insulates active and repressed genes within the Hox clusters upon differentiation, but such binding does not participate in boundary formation in all cell types, such as embryonic stem cells. We conducted a genome-wide CRISPR knockout screen to identify genes required for CTCF boundary activity at the HoxA cluster, complemented by novel biochemical approaches. This screen identified Myc-associated zinc finger protein (MAZ) as a CTCF insulator co-factor, among other candidates listed herein. MAZ depletion or specific deletion of MAZ motifs within the Hox clusters led to de-repression of posterior Hox genes immediately after CTCF boundaries upon differentiation, which phenocopied deletion of the proximal CTCF motifs. Similar to CTCF, MAZ interacted with the cohesin subunit, RAD21. Upon loss of MAZ, local contacts within topologically associated domains (TADs) were disrupted, as evidenced by HiC analysis. Thus, MAZ is a novel factor sharing insulation properties with CTCF and contributing to the genomic architectural organization. One Sentence SummaryMAZ is identified as an insulator functioning at CTCF boundaries delimiting active and repressed genes at Hox clusters

biochemistry↗

bioRxiv2018

Capturing the onset of PRC2-mediated repressive domain formation

Polycomb repressive complex 2 (PRC2) maintains gene silencing by catalyzing methylation of histone H3 at lysine 27 (H3K27me2/3) within chromatin. By designing a system whereby PRC2-mediated repressive domains were collapsed and then reconstructed in an inducible fashion in vivo, a two-step mechanism of H3K27me2/3 domain formation became evident. First, PRC2 is stably recruited by the actions of JARID2 and MTF2 to a limited number of spatially interacting \"nucleation sites\", creating H3K27me3-forming polycomb foci within the nucleus. Second, PRC2 is allosterically activated via its binding to H3K27me3 and rapidly spreads H3K27me2/3 both in cis and in far-cis via long-range contacts. As PRC2 proceeds further from the nucleation sites, its stability on chromatin decreases such that domains of H3K27me3 remain proximal, and those of H3K27me2 distal, to the nucleation sites. This study demonstrates the principles of de novo establishment of PRC2-mediated repressive domains across the genome.

genomics↗