Modulation of cellular processes by histone and non-histone protein acetylation

Genetic mutations and abnormal gene regulation are key mechanisms underlying tumorigenesis. Nucleosomes, which consist of DNA wrapped around histone cores, represent the basic units of chromatin. The fifth amino group (Ne) of histone lysine residues is a common site for post-translational modifications (PTMs), and of these, acetylation is the second most common. Histone acetylation is modulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs), and is involved in the regulation of gene expression. Over the past two decades, numerous studies characterizing HDACs and HDAC inhibitors (HDACi) have provided novel and exciting insights concerning their underlying biological mechanisms and potential anti-cancer treatments. In this review, we detail the diverse structures of HDACs and their underlying biological functions, including transcriptional regulation, metabolism, angiogenesis, DNA damage response, cell cycle, apoptosis, protein degradation, immunity and other several physiological processes. We also highlight potential avenues to use HDACi as novel, precision cancer treatments.

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The Roles of Histone Deacetylases and Their Inhibitors in Cancer Therapy.

Background Many metabolites serve as important signalling molecules to adjust cellular activities and functions based on nutrient availability. Links between acetyl-CoA metabolism, histone lysine acetylation, and gene expression have been documented and studied over the past decade. In recent years, several additional acyl modifications to histone lysine residues have been identified, which depend on acyl-coenzyme A thioesters (acyl-CoAs) as acyl donors. Acyl-CoAs are intermediates of multiple distinct metabolic pathways, and substantial evidence has emerged that histone acylation is metabolically sensitive. Nevertheless, the metabolic sources of acyl-CoAs used for chromatin modification in most cases remain poorly understood. Elucidating how these diverse chemical modifications are coupled to and regulated by cellular metabolism is important in deciphering their functional significance. Scope of review In this article, we review the metabolic pathways that produce acyl-CoAs, as well as emerging evidence for functional roles of diverse acyl-CoAs in chromatin regulation. Because acetyl-CoA has been extensively reviewed elsewhere, we will focus on four other acyl-CoA metabolites integral to major metabolic pathways that are also known to modify histones: succinyl-CoA, propionyl-CoA, crotonoyl-CoA, and butyryl-CoA. We also briefly mention several other acyl-CoA species, which present opportunities for further research; malonyl-CoA, glutaryl-CoA, 3-hydroxybutyryl-CoA, 2-hydroxyisobutyryl-CoA, and lactyl-CoA. Each acyl-CoA species has distinct roles in metabolism, indicating the potential to report shifts in the metabolic status of the cell. For each metabolite, we consider the metabolic pathways in which it participates and the nutrient sources from which it is derived, the compartmentalisation of its metabolism, and the factors reported to influence its abundance and potential nuclear availability. We also highlight reported biological functions of these metabolically-linked acylation marks. Finally, we aim to illuminate key questions in acyl-CoA metabolism as they relate to the control of chromatin modification. Major conclusions A majority of acyl-CoA species are annotated to mitochondrial metabolic processes. Since acyl-CoAs are not known to be directly transported across mitochondrial membranes, they must be synthesized outside of mitochondria and potentially within the nucleus to participate in chromatin regulation. Thus, subcellular metabolic compartmentalisation likely plays a key role in the regulation of histone acylation. Metabolite tracing in combination with targeting of relevant enzymes and transporters will help to map the metabolic pathways that connect acyl-CoA metabolism to chromatin modification. The specific function of each acyl-CoA may be determined in part by biochemical properties that affect its propensity for enzymatic versus non-enzymatic protein modification, as well as the various enzymes that can add, remove and bind each modification. Further, competitive and inhibitory effects of different acyl-CoA species on these enzymes make determining the relative abundance of acyl-CoA species in specific contexts important to understand the regulation of chromatin acylation. An improved and more nuanced understanding of metabolic regulation of chromatin and its roles in physiological and disease-related processes will emerge as these questions are answered.

Compartmentalised acyl-CoA metabolism and roles in chromatin regulation.

Histone post-translational modifications — cause and consequence of genome function

SIRT7, a sirtuin family member implicated in aging and disease, is a regulator of metabolism and stress responses. It remains elusive how human somatic stem cell populations might be impacted by SIRT7. Here, we found that SIRT7 expression declines during human mesenchymal stem cell (hMSC) aging and that SIRT7 deficiency accelerates senescence. Mechanistically, SIRT7 forms a complex with nuclear lamina proteins and heterochromatin proteins, thus maintaining the repressive state of heterochromatin at nuclear periphery. Accordingly, deficiency of SIRT7 results in loss of heterochromatin, de-repression of the LINE1 retrotransposon (LINE1), and activation of innate immune signaling via the cGAS-STING pathway. These aging-associated cellular defects were reversed by overexpression of heterochromatin proteins or treatment with a LINE1 targeted reverse-transcriptase inhibitor. Together, these findings highlight how SIRT7 safeguards chromatin architecture to control innate immune regulation and ensure geroprotection during stem cell aging.

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SIRT7 antagonizes human stem cell aging as a heterochromatin stabilizer

https://www.cell.com/molecular-cell/pdf/S1097-2765(19)30657-4.pdf

Glutarylation of Histone H4 Lysine 91 Regulates Chromatin Dynamics

Overexpression of transposable elements is associated with immune evasion and poor outcome in colorectal cancer

Objective The immune system plays a key role in protecting against cancer. Increased immune infiltration in tumor tissue is usually associated with improved clinical outcome, but in colorectal cancer (CRC), excessive immune infiltration has also been shown to lead to worst prognosis. The factors underlying this immune overdrive phenotype remains unknown. Design Using RNA sequencing data from The Cancer Genome Atlas, the expression of over 1,000 transposable element (TE) subfamilies were quantified using the “REdiscoverTE” pipeline. Candidate prognostic and immunogenic TEs were screened by survival and correlation analysis, respectively. Based on these candidates, a TE expression score was developed and CRC patients were clustered using the “kaps” algorithm. Results In CRC, we found that the TE expression score stratified patients into four clusters each with distinctive prognosis. Those with the highest TE expression were associated with immune overdrive and had the poorest outcomes. Importantly, this association was independent of microsatellite instability status and tumor mutation burden. To link TE overexpression to the immune overdrive phenotype, we showed that cell lines treated with DNA methyltransferase inhibitors also had a high TE expression score and activation of cellular innate immune response pathways. Finally, a pan-cancer survey of TE expression identified a subset of kidney renal clear cell carcinoma with a similar adverse immune overdrive phenotype with poor prognosis. Conclusion Our findings reveal that TE expression is associated with immune overdrive in cancer and is an independent predictor of immune infiltration and prognosis in CRC patients. 1. What is already known about this subject? Cancers with high immune infiltration generally have better prognosis, but it is unknown why a subset of colorectal cancers (CRC) with high immune infiltration have the poorest outcomes. Transposable element (TE) expression has been shown to be strongly associated with immune infiltration in cancers but its role in patient prognosis is unclear. TEs can be reactivated by DNA hypomethylation in cancers, resulting in immune response via viral mimicry. 2. What are the new findings? A TE expression score has been developed that is predicative of prognosis in CRC patients where those who have the highest TE score show an immune overdrive phenotype and have the worst prognosis. The TE expression score predicts prognostic and immune infiltration independent of microsatellite instability and tumor mutation burden (TMB). Immune response pathways and infiltrate profiles of high TE expression CRC recapitulates those of DNA methyltransferase inhibitor treated cells where TEs are reactivated, suggesting that TE overexpression may drive immune infiltration in CRC. A pan-cancer analysis found that kidney renal clear cell carcinoma shares are a similar TE expression associated immune overdrive phenotype with adverse prognosis. 3. How might it impact on clinical practice in the foreseeable future? Our work highlights the importance of TE expression in evaluating CRC patient prognosis. The association of TE expression with the immune overdrive phenotype independent of MSI and TMB status suggests that by considering TE expression, there may be new opportunities to identify MSS CRC patients for immunotherapy and develop new strategies to harness TE driven immune response.

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Kornelia Gladysz

Papers

Glutarylation of Histone H4 Lysine 91 Regulates Chromatin Dynamics

Overexpression of transposable elements is associated with immune evasion and poor outcome in colorectal cancer

Overexpression of transposable elements is associated with immune overdrive and poor clinical outcome in colorectal cancer patients