Biology subjects

Aitymbayev, D.

Publications and source records attributed to Aitymbayev, D..

2 recordsLinked to original sources

bioRxiv2024

Chemical perturbations impacting histone acetylation governcolorectal cancer differentiation

Dysregulated epigenetic programs that restrict differentiation, reactivate fetal genes, and confer phenotypic plasticity are critical to colorectal cancer (CRC) development. By screening a small molecule library targeting epigenetic regulators using our dual reporter system, we found that inhibiting histone deacetylase (HDAC) 1/2 promotes CRC differentiation and anti-tumor activity. Comprehensive biochemical, chemical, and genetic experiments revealed that on-target blockade of the HDAC1/2 catalytic domain mediated the differentiated phenotype. Unbiased profiling of histone posttranslational modifications induced by HDAC1/2 inhibition nominated acetylation of specific histone lysine residues as potential regulators of differentiation. Genome-wide assessment of implicated marks indicated that H3K27ac gains at HDAC1/2-bound regions associated with open chromatin and upregulation of differentiation genes upon HDAC1/2 inhibition. Disrupting H3K27ac by degrading acetyltransferase EP300 rescued HDAC1/2 inhibitor-mediated differentiation of a patient-derived CRC model using single cell RNA-sequencing. Genetic screens revealed that DAPK3 contributes to CRC differentiation induced by HDAC1/2 inhibition. These results highlight the importance of specific chemically targetable histone modifications in governing cancer cell states and epigenetic reprogramming as a therapeutic strategy in CRC. BRIEF SUMMARYHDAC1/2 inhibition promotes colorectal cancer differentiation via gains in H3K27ac, which can be reversed by blocking its acetyltransferase EP300.

cancer biology↗

bioRxiv2022

Developmental reprogramming mediates aberrant cell state plasticity in colorectal cancer initiation

Cell state (phenotypic) plasticity is a carefully regulated feature of adult epithelial cells that enables adaptive responses to injury, inflammation, and other forms of stress. Aberrant expansion of the normally restricted capability for cell state plasticity to escape terminal differentiation is a critical aspect of neoplasia. The nongenetic factors and specific programs that mediate aberrant cell state plasticity and impaired differentiation require deeper characterization to understand this elusive aspect of cancer pathogenesis. Using genetically engineered and carcinogen-induced murine models of intestinal neoplasia, we demonstrate that impaired differentiation is a conserved event preceding cancer development. Single cell RNA-sequencing (scRNA-seq) of neoplastic intestinal lesions from both mouse models and a patient with familial adenomatous polyposis revealed that cancer initiates by adopting an aberrant transcriptional state characterized by nonoverlapping expression of a regenerative pathway, marked by Ly6a (Sca-1), and a fetal intestinal program, positive for Tacstd2 (Trop2). Genetic inactivation of Sox9 prevented adenoma formation in ApcKO mice, obstructed emergence of aberrant regenerative and fetal intestinal programs, and restored multi-lineage differentiation by scRNA-seq. Expanded chromatin accessibility at regeneration and fetal genes upon Apc inactivation was reduced by concomitant Sox9 suppression. These studies indicate that aberrant cell state plasticity mediated by unabated regenerative activity and developmental reprogramming precedes cancer development.

cancer biology↗