Epigenetic mechanisms of mammalian tissue aging

National Institute On Aging

Investigators

Linked publications, trials & patents

Abstract

Chromatin analysis of the aging and regenerating liver The liver is the primary metabolic organ in vertebrates and various liver diseases including non-alcoholic fatty liver disease, fibrosis, and cirrhosis are correlated with aging. A remarkable feature of the liver is its capacity to regenerate following injury, but this is compromised with age. Our lab has been using the liver as a model organ to investigate chromatin changes in aging and further, liver regeneration as an in vivo paradigm to study the reversibility of these changes. We aim to compile this information to identify key drivers of aging and develop chromatin-focused therapeutics. Our work in the liver has diverged in two directions, one focusing on a histone modification and another focusing on a DNA modification. Chromatin dynamics in quiescent and activated muscle stem cells Skeletal muscle is another metabolically active organ showing profound loss of function and regeneration with age, partially due to the attenuation in muscle stem cell (MuSC) number and function35. With age, mice show significant loss in muscle mass (sarcopenia) as in humans, despite gain in body weight. Although the transcriptome and MuSC niche in aging tissues has been probed extensively, technical limitations have limited the investigation of chromatin in MuSCs directly, partly due to their limited number. We adopted low-input chromatin profiling strategies to map multiple hPTMs, chromatin accessibility, transcriptome, and 3D genome in young and old MuSCs, both in the quiescent state (QMuSCs) and upon activation via chemical injury (AMuSCs). An integrated analysis of these data has begun to provide a comprehensive understanding of how the altered epigenome in tissue-resident stem cells directly compromise organ regenerative function in aging. Chromatin and transcriptional analyses of the aging brain Aging is accompanied by cognitive deficits, but the molecular etiology of age-related cognitive decline is poorly understood. Toward this direction, we initiated a comprehensive spatiotemporal profiling of the cellular and molecular landscape in aging murine brains of both sexes. Our expectation was that spatial transcriptomics will reveal mRNA differences, paracrine signaling, and cellular networks not captured in averaged spatially naive analyses of homogenized biopsies. In a related project, we are parallelly investigating the role of histone acetylation in preserving age-related cognitive function. It is well documented that acetylation/deacetylation of histone tails play a prominent role in learning and memory. Two paralogous histone acetyltransferases (HATs), the E1A-associated protein p300 (p300) and CREB-binding protein (CBP), have been implicated in the molecular mechanisms underlying memory formation45 and are the only HATs mediating H3K27 acetylation at enhancers. Recent published studies in human post-mortem brains suggest that p300/CBP-mediated histone acetylation drives Alzheimers disease (AD) pathways by driving disease-specific gene expression30. Given the critical (and somewhat different) roles of these HATs in the normal and pathological brain, we became interested to pursue this direction. We ultimately aim to design therapeutic avenues targeting these HATs to ameliorate cognitive deficits. In fiscal year 2023, we have continued our investigations as outlined in the directions above. In the liver, we have generated multiple multi-omic datasets and published our findings (Yang et al, 2023). We have collaborated with Dr. Vittorio Sartorelli to isolate muscle stem cells with FACS and have generated CUT&RUN, RNA-seq, ATAC-seq and HiC data. We are currently analyzing these datasets. In the brain, we have generated spatial transcriptomics datasets from young, middle-aged, and old mice and identified key brain regions that are prone to age-related neuroinflammation. To probe the role of histone acetylation in age-related loss of learning and memory, we have performed stereotaxic injections knocking out p300/CBP in young and old mice hippocampi and identified these as key enzymes contributing to age-related cognitive decline. Integration of these multi-omic, phenotypic, and behavioral datasets will provide key insights into the molecular mechanisms of tissue aging.