Nutrient Sensing by Histone Marks: Reading the Metabolic Histone Code Using Tracing, Omics, and Modeling

Campit, Scott; Meliki, Alia; Youngson, Neil A.; Chandrasekaran, Sriram

doi:10.1002/bies.202000083

Cited by 11 publications

(11 citation statements)

References 106 publications

(150 reference statements)

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“…Genome-scale metabolic models have been widely used to predict the metabolic behaviour of various mammalian cell types using transcriptomics data 49,50 . Gene expression data from mouse hepatocyte AML12 cells treated with fatty acids (Octanoate) from McDonnel et al 13 was used as input to derive reaction flux through the human genome-scale metabolic model (RECONI) 29 .…”

Section: Methodsmentioning

confidence: 99%

Acetyl-CoA metabolism drives epigenome change and contributes to carcinogenesis risk in fatty liver disease

Assante

Chandrasekaran

et al. 2021

Preprint

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The rate of nonalcoholic fatty liver disease (NAFLD)-associated hepatocellular carcinoma (HCC) is increasing worldwide, but the steps in precancerous hepatocytes which lead to HCC driver mutations are not well understood. Here we provide evidence that metabolically-driven histone hyperacetylation in steatotic hepatocytes can increase DNA damage to initiate carcinogenesis. Genome-wide histone acetylation is increased in steatotic livers of rodents fed high fructose or high fat diet. In vitro, steatosis relaxes chromatin and increases DNA damage marker γH2AX, which is reversed by inhibiting acetyl-CoA production. Steatosis-associated acetylation and γH2AX are enriched at gene clusters in telomere-proximal regions which contain HCC tumor suppressors in hepatocytes and human fatty livers. Regions of metabolically-driven epigenetic change also have increased levels of DNA mutation in non-cancerous tissue from NAFLD patients. Finally, genome-scale network modelling indicates that redox balance is a key contributor to this mechanism. Thus abnormal histone hyperacetylation is a potential initiating event in HCC carcinogenesis.

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Section: Methodsmentioning

confidence: 99%

Acetyl-CoA metabolism drives epigenome change and contributes to carcinogenesis risk in fatty liver disease

Assante

Chandrasekaran

et al. 2021

Preprint

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“…GEMs potentially offer a framework for measuring how metabolism interacts with epigenetics [ 77 , 78 ]. However, a major limitation of using GEMs is the fact that key reactions involved in epigenetic regulation, such as those transporting or synthesizing metabolites such as Acetyl-CoA in the nucleus, are often missing.…”

Section: Modeling Of Metabolic Regulationmentioning

confidence: 99%

Next-Generation Genome-Scale Metabolic Modeling through Integration of Regulatory Mechanisms

et al. 2021

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Genome-scale metabolic models (GEMs) are powerful tools for understanding metabolism from a systems-level perspective. However, GEMs in their most basic form fail to account for cellular regulation. A diverse set of mechanisms regulate cellular metabolism, enabling organisms to respond to a wide range of conditions. This limitation of GEMs has prompted the development of new methods to integrate regulatory mechanisms, thereby enhancing the predictive capabilities and broadening the scope of GEMs. Here, we cover integrative models encompassing six types of regulatory mechanisms: transcriptional regulatory networks (TRNs), post-translational modifications (PTMs), epigenetics, protein–protein interactions and protein stability (PPIs/PS), allostery, and signaling networks. We discuss 22 integrative GEM modeling methods and how these have been used to simulate metabolic regulation during normal and pathological conditions. While these advances have been remarkable, there remains a need for comprehensive and widespread integration of regulatory constraints into GEMs. We conclude by discussing challenges in constructing GEMs with regulation and highlight areas that need to be addressed for the successful modeling of metabolic regulation. Next-generation integrative GEMs that incorporate multiple regulatory mechanisms and their crosstalk will be invaluable for discovering cell-type and disease-specific metabolic control mechanisms.

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“…A high nuclear pool of acetate would promote acetylation. Like other epigenetic modulation mechanisms, histone modifications starts right from embryogenesis and dynamically continue/reshape throughout the lifespan; thus besides environmental stimuli, it could be influenced by mother's diet right in the womb and reversibly continues [172][173][174][175][176].…”

Section: Epigenetic Modulations Nutrients Bioactive Food Compounds Microbiota and Cancermentioning

confidence: 99%

Reviewing cancer’s biology: an eclectic approach

Karidio

Şanlıer

2021

J Egypt Natl Canc Inst

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Background Cancer refers to a group of some of the worldwide most diagnosed and deadliest pathophysiological conditions that conquered researchers’ attention for decades and yet begs for more questions for a full comprehension of its complex cellular and molecular pathology. Main body The disease conditions are commonly characterized by unrestricted cell proliferation and dysfunctional replicative senescence pathways. In fact, the cell cycle operates under the rigorous control of complex signaling pathways involving cyclins and cyclin-dependent kinases assumed to be specific to each phase of the cycle. At each of these checkpoints, the cell is checked essentially for its DNA integrity. Genetic defects observed in these molecules (i.e., cyclins, cyclin-dependent kinases) are common features of cancer cells. Nevertheless, each cancer is different concerning its molecular and cellular etiology. These could range from the genetic defects mechanisms and/or the environmental conditions favoring epigenetically harbored homeostasis driving tumorigenesis alongside with the intratumoral heterogeneity with respect to the model that the tumor follows. Conclusions This review is not meant to be an exhaustive interpretation of carcinogenesis but to summarize some basic features of the molecular etiology of cancer and the intratumoral heterogeneity models that eventually bolster anticancer drug resistance for a more efficient design of drug targeting the pitfalls of the models.

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Nutrient Sensing by Histone Marks: Reading the Metabolic Histone Code Using Tracing, Omics, and Modeling

Cited by 11 publications

References 106 publications

Acetyl-CoA metabolism drives epigenome change and contributes to carcinogenesis risk in fatty liver disease

Acetyl-CoA metabolism drives epigenome change and contributes to carcinogenesis risk in fatty liver disease

Next-Generation Genome-Scale Metabolic Modeling through Integration of Regulatory Mechanisms

Reviewing cancer’s biology: an eclectic approach

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