bims-meprid 2021-02-28 papers

Bioessays. 2021 Feb 25. e2000273

Metabolism and chromatin: A dynamic duo that regulates development and ageing: Elucidating the metabolism-chromatin axis in bone-marrow mesenchymal stem cell fate decisions.

Andromachi Pouikli, Peter Tessarz.

Bone-marrow mesenchymal stem cell (BM-MSC) proliferation and lineage commitment are under the coordinated control of metabolism and epigenetics; the MSC niche contains low oxygen, which is an important determinant of the cellular metabolic state. In turn, metabolism drives stem cell fate decisions via alterations of the chromatin landscape. Due to the fundamental role of BM-MSCs in the development of adipose tissue, bones and cartilage, age-associated changes in metabolism and the epigenome perturb the balance between stem cell proliferation and differentiation leading to stem cell depletion, fat accumulation and bone-quality related diseases. Therefore, understanding the dynamics of the metabolism-chromatin interplay is crucial for maintaining the stem cell pool and delaying the development and progression of ageing. This review summarizes the current knowledge on the role of metabolism in stem cell identity and highlights the impact of the metabolic inputs on the epigenome, with regards to stemness and pluripotency.

Keywords: ageing; differentiation; epigenetics; mesenchymal stem cells; metabolism

DOI: https://doi.org/10.1002/bies.202000273

Sci Adv. 2021 Feb;pii: eabe2771. [Epub ahead of print]7(9):

The regulatory enzymes and protein substrates for the lysine β-hydroxybutyrylation pathway.

He Huang, Di Zhang, Yejing Weng, Kyle Delaney, Zhanyun Tang, Cong Yan, Shankang Qi, Chao Peng, Philip A Cole, Robert G Roeder, Yingming Zhao.

Metabolism-mediated epigenetic changes represent an adapted mechanism for cellular signaling, in which lysine acetylation and methylation have been the historical focus of interest. We recently discovered a β-hydroxybutyrate-mediated epigenetic pathway that couples metabolism to gene expression. However, its regulatory enzymes and substrate proteins remain unknown, hindering its functional study. Here, we report that the acyltransferase p300 can catalyze the enzymatic addition of β-hydroxybutyrate to lysine (Kbhb), while histone deacetylase 1 (HDAC1) and HDAC2 enzymatically remove Kbhb. We demonstrate that p300-dependent histone Kbhb can directly mediate in vitro transcription. Moreover, a comprehensive analysis of Kbhb substrates in mammalian cells has identified 3248 Kbhb sites on 1397 substrate proteins. The dependence of histone Kbhb on p300 argues that enzyme-catalyzed acylation is the major mechanism for nuclear Kbhb. Our study thus reveals key regulatory elements for the Kbhb pathway, laying a foundation for studying its roles in diverse cellular processes.

DOI: https://doi.org/10.1126/sciadv.abe2771

Nat Metab. 2021 Feb;3(2): 196-210

Murine neonatal ketogenesis preserves mitochondrial energetics by preventing protein hyperacetylation.

Ketone bodies are generated in the liver and allow for the maintenance of systemic caloric and energy homeostasis during fasting and caloric restriction. It has previously been demonstrated that neonatal ketogenesis is activated independently of starvation. However, the role of ketogenesis during the perinatal period remains unclear. Here, we show that neonatal ketogenesis plays a protective role in mitochondrial function. We generated a mouse model of insufficient ketogenesis by disrupting the rate-limiting hydroxymethylglutaryl-CoA synthase 2 enzyme gene (Hmgcs2). Hmgcs2 knockout (KO) neonates develop microvesicular steatosis within a few days of birth. Electron microscopic analysis and metabolite profiling indicate a restricted energy production capacity and accumulation of acetyl-CoA in Hmgcs2 KO mice. Furthermore, acetylome analysis of Hmgcs2 KO cells revealed enhanced acetylation of mitochondrial proteins. These findings suggest that neonatal ketogenesis protects the energy-producing capacity of mitochondria by preventing the hyperacetylation of mitochondrial proteins.

DOI: https://doi.org/10.1038/s42255-021-00342-6

J Trace Elem Med Biol. 2021 Feb 12. pii: S0946-672X(21)00021-3. [Epub ahead of print]65 126731

Effect of maternal zinc deficiency on offspring health: The epigenetic impact.

Kamaldeen Olalekan Sanusi, Kasimu Ghandi Ibrahim, Bilyaminu Abubakar, Ibrahim Malami, Muhammad Bashir Bello, Mustapha Umar Imam, Murtala Bello Abubakar.

BACKGROUND: Zinc deficiency is associated with adverse effects on maternal health and pregnancy outcomes. These consequences have been reported over the years from zinc supplementation trials and observational studies whereby outcomes of maternal, foetal and infant health were measured. Owing to the importance of zinc in the functions of epigenetic enzymes, pre-clinical studies have shown that its deficiency could disrupt biological activities that involve epigenetic mechanisms in offspring. Thus, this review assessed the link between epigenetics and the effects of maternal zinc deficiency on the offspring's health in animal studies.
METHODS: Research articles were retrieved without date restriction from PubMed, Web of Science, ScienceDirect, and Google Scholar databases, as well as reference lists of relevant articles. The search terms used were "zinc deficiency", "maternal zinc deficiency", "epigenetics", and "offspring." Six studies met the eligibility criteria and were reviewed.
RESULTS: All the eligible studies reported maternal zinc deficiency and observed changes in epigenetic markers on the progeny during prenatal and postnatal stages of development. The main epigenetic markers reported were global and gene specific methylation and/ or acetylation. The epigenetic changes led to mortality, disruption in development, and risk of later life diseases.
CONCLUSION: Maternal zinc deficiency is associated with epigenetic modifications in offspring, which induce pathologies and increase the risk of later life diseases. More research and insight into the epigenetic mechanisms could spring up new approaches to combat the associated disease conditions.

Keywords: DNA methylation; Epigenetics; Histone modification; Maternal zinc deficiency; Offspring

DOI: https://doi.org/10.1016/j.jtemb.2021.126731