Biology subjects

Tian, T. V.

Publications and source records attributed to Tian, T. V..

4 recordsLinked to original sources

bioRxiv2022

Carm1 regulates the speed of C/EBPa-induced transdifferentiation by a cofactor stealing mechanism

Cell fate decisions are driven by lineage-restricted transcription factors but how they are regulated is incompletely understood. The C/EBP-induced B cell to macrophage transdifferentiation (BMT) is a powerful system to address this question. Here we describe that C/EBP with a single arginine mutation (C/EBPR35A) induces a dramatically accelerated BMT in mouse and human cells. Changes in the expression of lineage-restricted genes occur as early as within 1 hour compared to 18 hours with the wild type. Mechanistically C/EBPR35A exhibits an increased affinity for PU.1, a bi-lineage transcription factor required for C/EBP-induced BMT. The complex induces more rapid chromatin accessibility changes and an enhanced relocation (stealing) of PU.1 from B cell to myeloid gene regulatory elements. Arginine 35 is methylated by Carm1 and inhibition of the enzyme accelerates BMT, similar to the mutant. Our data suggest that the relative proportions of methylated and unmethylated C/EBP in a bipotent progenitor can determine the velocity of cell fate choice and lineage directionality.

cell biology↗

bioRxiv2022

The BRD4S-LOXL2-MED1 interaction at the forefront of cell cycle transcriptional control in triple-negative breast cancer

Triple-negative breast cancer often develops resistance to single-agent treatments, which can be circumvented with targeted combinatorial approaches. Here, we demonstrate that the simultaneous inhibition of LOXL2 and BRD4 cooperate to reduce triple-negative breast cancer proliferation in vitro and in vivo. Mechanistically, we reveal that LOXL2 interacts in the nucleus with the short isoform of BRD4 and MED1 to control cell cycle progression at the gene expression level via sustaining the formation of BRD4-MED1 nuclear transcriptional foci. Indeed, the pharmacological or transcriptional repression of LOXL2 provokes downregulation of cell cycle gene expression, G1-S cell cycle arrest, and loss of BRD4-MED1 foci. Our results indicate that the BRD4S-LOXL2-MED1 interaction is fundamental for the proliferation of triple-negative breast cancer. Therefore, targeting such interaction holds potential for the development of novel triple-negative breast cancer therapies.

cancer biology↗

bioRxiv2022

The RNA-Binding Protein SAM68 regulates cardiomyocyte differentiation by enhancing Gata4 translation

The signal transduction and activation of RNA (STAR) family is composed of RNA-binding proteins (RBPs) that play a central role in mammalian development. Nonetheless, the functions and modes of action that STAR proteins have in lineage specification are still poorly understood. Here, we characterized the role of STAR proteins SAM68 and QUAKING (QKI) in pluripotency and differentiation by performing their depletion through CRISPR-Cas9 in mouse embryonic stem cells (mESCs). Combining RNA-sequencing, ribosome profiling and advanced computational predictions, we found that both SAM68 and QKI regulate the mESCs self-renewal and are indispensable for cardiomyocyte differentiation. At the molecular level, we discovered that SAM68 and QKI antagonistically control the expression of cardiogenic factors. Our calculations indicated that SAM68, unlike QKI, binds the cardiogenic-specific transcription factor Gata4 in a region spanning nucleotides 500 to 1000 of the mRNA corresponding to part of the 5 untranslated region and the first exon. We validated the predictions by electrophoretic mobility shift assay and RNA immunoprecipitation showing that SAM68 controls the translation of Gata4 during mESCs differentiation towards the cardiomyocyte lineage.

molecular biology↗

bioRxiv2020

Maintaining oxidized H3 in heterochromatin is required for the oncogenic capacity of triple-negative breast cancer cells

The histone modification of H3 oxidized at lysine 4 (H3K4ox) is catalyzed by lysyl oxidase-like 2 (LOXL2) and is enriched in heterochromatin in triple-negative breast cancer (TNBC) cells. Although H3K4ox has been linked to the maintenance of compacted chromatin, the molecular mechanism underlying this maintenance is unknown. Here we show that H3K4ox is read by the CRL4B complex, leading to the ubiquitination of histone H2A through the E3 ligase RBX1. Finally, interactions between RUVBL1/2 and LOXL2 are involved in the incorporation of the histone variant H2A.Z, which plays an essential role in the mechanism controlling the dynamics of oxidized H3. Maintenance of H3K4ox in chromatin is essential for heterochromatin properties, and disruption of any of the members involved in this pathway blocks the oncogenic properties of TNBC cells.

cancer biology↗