Biology subjects

Bozukova, M.

Publications and source records attributed to Bozukova, M..

2 recordsLinked to original sources

bioRxiv2022

Reduced polymerase pausing compensates for increased chromatin accessibility in the aging liver

Regulation of gene expression is tightly linked to the organization of the mammalian genome. With age, chromatin alterations occur on all levels of genome organization, accompanied by changes in the gene expression profile. However, little is known about the changes on the level of transcriptional regulation with age. Here, we used a multi-omic approach and integrated ATAC-, RNA- and NET-seq to identify age-related changes in the chromatin landscape of murine liver and to investigate how these are linked to transcriptional regulation. We provide the first systematic inventory of the connection between aging, chromatin accessibility and transcriptional regulation in a whole tissue. We observe that aging in murine liver is accompanied by an increase in chromatin accessibility at promoter regions of protein-coding genes. Yet, although promoter accessibility is a requirement for transcription, the increased accessibility does not result in enhanced transcriptional output. Instead, aging is accompanied by a decrease of promoter-proximal pausing of RNA polymerase II (Pol II). We propose that these changes in transcriptional regulation are due to a reduced stability of the pausing complex and may represent a mechanism to compensate for the age-related increase in chromatin accessibility in order to prevent aberrant transcription.

molecular biology↗

bioRxiv2021

Single-cell resolution unravels spatial alterations in metabolism, transcriptome and epigenome of ageing liver

Epigenetic ageing clocks have revealed that tissues within an organism can age with different velocity. However, it has not been explored whether cells of one type experience different ageing trajectories within a tissue depending on their location. Here, we employed lipidomics, spatial transcriptomics and single-cell ATAC-seq in conjunction with available single-cell RNA-seq data to address how cells in the murine liver are affected by age-related changes of the microenvironment. Integration of the datasets revealed zonation-specific and age-related changes in metabolic states, the epigenome and transcriptome. Particularly periportal hepatocytes were characterized by decreased mitochondrial function and strong alterations in the epigenetic landscape, while pericentral hepatocytes - despite accumulation of large lipid droplets - did not show apparent functional differences. In general, chromatin alterations did not correlate well with transcriptional changes, hinting at post-transcriptional processes that shape gene expression during ageing. Together, we provide evidence that changing microenvironments within a tissue exert strong influences on their resident cells that can shape epigenetic, metabolic and phenotypic outputs.

cell biology↗