Biology subjects

Lazarenkov, A.

Publications and source records attributed to Lazarenkov, A..

3 recordsLinked to original sources

bioRxiv2024

Modulating immune cell fate and inflammation through CRISPR-mediated DNA methylation editing

DNA methylation is traditionally associated with gene silencing, but its causal relationship and role in shaping cell fate decisions still need to be fully elucidated. Here, we conducted a genome-wide analysis to investigate the relationship between DNA methylation and gene expression at gene regulatory regions in human immune cells. By utilizing CRISPR-dCas9 DNA methylation editing tools, we successfully established a cause-and-effect relationship between the methylation levels of the promoter of the Interleukin1-receptor antagonist (IL1RN) gene and its expression. Notably, we observed that modifying the DNA methylation status of the IL1RN promoter is sufficient to alter the acquisition of the human myeloid cell fate and change the cellular response to inflammatory stimuli, resulting in abnormal cytokine release and distinctive capacity to support cancer growth.

genomics↗

bioRxiv2023

p53 rapidly restructures 3D chromatin organization to trigger a transcriptional response

Activation of the p53 tumor suppressor triggers a transcriptional program to control cellular response to stress. However, the molecular mechanisms by which p53 controls gene transcription are not completely understood. Here, using a multi-omics integration framework, we uncover the critical role of spatio-temporal genome architecture in this process. We demonstrate that p53 drives direct and indirect changes in genome compartments, topologically associating domains and DNA loops within minutes of its activation, which escort the p53 transcriptional program along time. Focused on p53-bound enhancers, we report a core transcriptional program of 340 genes directly regulated by p53 over distance, most of these not previously identified. Finally, we showcase that p53 controls transcription of distal genes through newly formed and pre-existing enhancer-promoter loops in a cohesin dependent manner. Taken together, our findings demonstrate a previously unappreciated architectural role of p53 as regulator at distinct topological layers and provide a reliable set of new p53 direct target genes that may help future designs of p53-based cancer therapies.

genomics↗

bioRxiv2023

The Interferon gamma Pathway Enhances Pluripotency and X-Chromosome Reactivation in iPSC Reprogramming

Reprogramming somatic cells into induced pluripotent stem cells (iPSCs) requires activation of the pluripotency network and resetting of the epigenome by erasing the epigenetic memory of the somatic state. In female mouse cells, a critical epigenetic reprogramming step is the reactivation of the inactive X chromosome. Despite its importance, a systematic understanding of the regulatory networks linking pluripotency and X-reactivation is missing. Here we reveal the pathways important for iPSC reprogramming and X-reactivation using a genome-wide CRISPR screen. In particular, we discover that activation of the interferon {gamma} (IFN{gamma}) pathway early during reprogramming accelerates pluripotency acquisition and X-reactivation. IFN{gamma} stimulates STAT3 signaling and the pluripotency network and leads to enhanced TET-mediated DNA demethylation, which consequently boosts X-reactivation. We therefore gain a mechanistic understanding of the role of IFN{gamma} in reprogramming and X-reactivation and provide a comprehensive resource of the molecular networks involved in these processes.

genetics↗