Aging is associated with increased chromatin accessibility and reduced polymerase pausing in liver

Abstract

Regulation of gene expression is linked to the organization of the 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 in the level of transcriptional regulation. Here, we used a multi‐omics 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. Aging in murine liver is characterized by an increase in chromatin accessibility at promoter regions, but not in an increase in transcriptional output. Instead, aging is accompanied by a decrease in promoter‐proximal pausing of RNA polymerase II (Pol II), while initiation of transcription is not decreased as assessed by RNA polymerase mapping using CUT&RUN. Based on the data reported, we propose that these age‐related changes in transcriptional regulation are due to a reduced stability of the pausing complex.

Impaired biogenesis of basic proteins impacts multiple hallmarks of the aging brain

“…This phenomenon, caused by the presence of basic amino acids in their protein sequences, likely has a direct impact on each step of the gene expression process, and could mechanistically connect proteostasis impairment to other canonical aging hallmarks, including DNA damage, epigenetic alterations (35), aberrant splicing (36) and reduced RNA polymerase activity (37). Of note, individual manipulation of protein biosynthesis, as well as any of these pathways, ameliorates aging phenotypes (37)(38)(39)(40)(41)(42)43), further highlighting their central role in the aging process. A second implication is that aging leads to altered mitochondrial composition, partially driven by a reduced ribosomal content.…”

The Road Less Traveled: Uncovering the Convergence Toward Specific Pleiotropic Phenotypes in Aging

“…However, the ability of RNA polymerase to complete its trip, and hence the production of a nascent transcript molecule, could be hindered by many factors, such as impaired function of RNA polymerase itself 21 , DNA breaks 8,23 , polymerase stalling 9 , epigenetic consequences of methylated DNA 20 , and DNA supercoiling 18,24 . Furthermore, RNA polymerase speed increases in aging 25,26 , and cryptic polyadenylation sites no longer being masked by telescripting due to increased RNA polymerase speeds 15 could be viewed as corresponding to a car no longer being able to follow permitted speed limits and hence having an increased probability of being policed out of traffic (Figure 1A). The absence of any incidence that prevents the completion of a road trip, scales exponentially with the travelled distance, and a constant increase in the failure rate hence disproportionately affects long trips (Figure 1B,C).…”

“…Furthermore, RNA polymerase speed increases in aging 25,26 , and cryptic polyadenylation sites no longer being masked by telescripting due to increased RNA polymerase speeds 15 could be viewed as corresponding to a car no longer being able to follow permitted speed limits and hence having an increased probability of being policed out of traffic (Figure 1A). The absence of any incidence that prevents the completion of a road trip, scales exponentially with the travelled distance, and a constant increase in the failure rate hence disproportionately affects long trips (Figure 1B,C).…”

Keep calm and transcribe on: chromatin changes with age, but transcription can learn to live with it

“…This is followed by the recruitment and assembly of RNA Pol II on the target gene and, lastly, RNA Pol II is released into productive elongation, a process that is intricately regulated. In a tour de force, Bozukova et al assess each of these stages for all transcribed genes, in liver tissue from young and old mice (Bozukova et al , 2022 ). They then integrate the genome‐wide information, assembling a comprehensive overview of age‐associated changes.…”

“…Assessing age-related tissue dysfunction represents an emerging field and involves analyses that are far from trivial, often requiring the integration of several largescale ("omic") techniques. In their recent work, Tessarz and colleagues (Bozukova et al, 2022) characterize changes in the transcriptional machinery during aging in mice and report some surprising findings. T issue function declines with ageperhaps one of the earliest and simplest biological observations.…”