A two-way relationship between histone acetylation and metabolism.

A link between epigenetics and metabolism was initially recognized because the cellular metabolic state is communicated to the genome through the concentration of intermediary metabolites that are cofactors of chromatin-modifying enzymes. Recently, an additional interaction was postulated due to the capacity of the epigenome to store substantial amounts of metabolites that could become available again to cellular metabolite pools. Here, we focus on histone acetylation and review recent evidence illustrating this reciprocal relationship: in one direction, signaling-induced acetyl-coenzyme A (acetyl-CoA) changes influence histone acetylation levels to regulate genomic functions, and in the opposite direction histone acetylation acts as an acetate reservoir to directly affect downstream acetyl-CoA-mediated metabolism.

Yeast Nat4 regulates DNA damage checkpoint signaling through its N-terminal acetyltransferase activity on histone H4.

The DNA damage response (DDR) constitutes a vital cellular process that safeguards genome integrity. This biological process involves substantial alterations in chromatin structure, commonly orchestrated by epigenetic enzymes. Here, we show that the epigenetic modifier N-terminal acetyltransferase 4 (Nat4), known to acetylate the alpha-amino group of serine 1 on histones H4 and H2A, is implicated in the response to DNA damage in S.

Hyperacetylated histone H4 is a source of carbon contributing to lipid synthesis.

Histone modifications commonly integrate environmental cues with cellular metabolic outputs by affecting gene expression. However, chromatin modifications such as acetylation do not always correlate with transcription, pointing towards an alternative role of histone modifications in cellular metabolism. Using an approach that integrates mass spectrometry-based histone modification mapping and metabolomics with stable isotope tracers, we demonstrate that elevated lipids in acetyltransferase-depleted hepatocytes result from carbon atoms derived from deacetylation of hyperacetylated histone H4 flowing towards fatty acids.

Cellular effects of NAT-mediated histone N-terminal acetylation.

Histone acetylation involves the addition of acetyl groups to specific amino acid residues. This chemical histone modification is broadly divided into two types - acetylation of the amino group found on the side chain of internal lysine residues (lysine acetylation) or acetylation of the α-amino group at the N-terminal amino acid residue (N-terminal acetylation). Although the former modification is considered a classic epigenetic mark, the biological importance of N-terminal acetylation has been mostly overlooked in the past, despite its widespread occurrence and evolutionary conservation.

Histone methylation in pre-cancerous liver diseases and hepatocellular carcinoma: recent overview.

Hepatocellular carcinoma (HCC) is the prevalent form of liver cancer in adults and the fourth most common cause of cancer-related death worldwide. HCC predominantly arises in the context of cirrhosis as a result of chronic liver disease, injury and inflammation. Full-blown HCC has poor prognosis because it is highly aggressive and resistant to therapy.

Quantitative RNA imaging in single live cells reveals age-dependent asymmetric inheritance.

Asymmetric inheritance of cellular content through cell division plays an important role in cell viability and fitness. The dynamics of RNA segregation are so far largely unaddressed. This is partly due to a lack of approaches to follow RNAs over multiple cellular divisions.

Histone acetyltransferase NAA40 modulates acetyl-CoA levels and lipid synthesis.

Background: Epigenetic regulation relies on the activity of enzymes that use sentinel metabolites as cofactors to modify DNA or histone proteins. Thus, fluctuations in cellular metabolite levels have been reported to affect chromatin modifications. However, whether epigenetic modifiers also affect the levels of these metabolites and thereby impinge on downstream metabolic pathways remains largely unknown.

Histone N-terminal acetyltransferase NAA40 links one-carbon metabolism to chemoresistance.

Aberrant function of epigenetic modifiers plays an important role not only in the progression of cancer but also the development of drug resistance. N-alpha-acetyltransferase 40 (NAA40) is a highly specific epigenetic enzyme catalyzing the transfer of an acetyl moiety at the N-terminal end of histones H4 and H2A. Recent studies have illustrated the essential oncogenic role of NAA40 in various cancer types but its role in chemoresistance remains unclear.

Identification of NAA40 as a Potential Prognostic Marker for Aggressive Liver Cancer Subtypes.

Liver hepatocellular carcinoma (LIHC) is a leading cause of cancer-related mortality. In this study we initially interrogated the Cancer Genome Atlas (TCGA) dataset to determine the implication of N-terminal acetyltransferases (NATs), a family of enzymes that modify the N-terminus of the majority of eukaryotic proteins, in LIHC. This examination unveiled NAA40 as the NAT family member with the most prominent upregulation and significant disease prognosis for this cancer.

Microfluidics for single-cell lineage tracking over time to characterize transmission of phenotypes in .

The budding yeast is an excellent model organism to dissect the maintenance and inheritance of phenotypes due to its asymmetric division. This requires following individual cells over time as they go through divisions to define pedigrees. Here, we provide a detailed protocol for collecting and analyzing time-lapse imaging data of yeast cells.

N-Terminal Acetyltransferases Are Cancer-Essential Genes Prevalently Upregulated in Tumours.

N-terminal acetylation (Nt-Ac) is an abundant eukaryotic protein modification, deposited in humans by one of seven N-terminal acetyltransferase (NAT) complexes composed of a catalytic and potentially auxiliary subunits. The involvement of NATs in cancers is being increasingly recognised, but a systematic cross-tumour assessment is currently lacking. To address this limitation, we conducted here a multi-omic data interrogation for NATs.

The past determines the future: sugar source history and transcriptional memory.

Transcriptional reinduction memory is a phenomenon whereby cells "remember" their transcriptional response to a previous stimulus such that subsequent encounters with the same stimulus can result in altered gene expression kinetics. Chromatin structure is thought to play a role in certain transcriptional memory mechanisms, leading to questions as to whether and how memory can be actively maintained and inherited to progeny through cell division. Here we summarize efforts towards dissecting chromatin-based transcriptional memory inheritance of GAL genes in Saccharomyces cerevisiae.

Synthetic dosage lethal (SDL) interaction data of Hmt1 arginine methyltransferase.

The introduction of methyl groups on arginine residues is catalysed by Protein Arginine Methyltransferases (PRMTs). However, the regulatory mechanisms that dictate the levels of protein arginine methylation within cells are still not completely understood. We employed Synthetic Dosage Lethality (SDL) screening in , for the identification of putative regulators of arginine methylation mediated by Hmt1 (HnRNP methyltransferase 1), ortholog of human PRMT1.

Single-Cell Tracing Dissects Regulation of Maintenance and Inheritance of Transcriptional Reinduction Memory.

Transcriptional memory of gene expression enables adaptation to repeated stimuli across many organisms. However, the regulation and heritability of transcriptional memory in single cells and through divisions remains poorly understood. Here, we combined microfluidics with single-cell live imaging to monitor Saccharomyces cerevisiae galactokinase 1 (GAL1) expression over multiple generations.

Histone Modifications as an Intersection Between Diet and Longevity.

Histone modifications are key epigenetic regulators that control chromatin structure and gene transcription, thereby impacting on various important cellular phenotypes. Over the past decade, a growing number of studies have indicated that changes in various histone modifications have a significant influence on the aging process. Furthermore, it has been revealed that the abundance and localization of histone modifications are responsive to various environmental stimuli, such as diet, which can also affect gene expression and lifespan.

NAA40 contributes to colorectal cancer growth by controlling PRMT5 expression.

N-alpha-acetyltransferase 40 (NAA40) catalyzes the transfer of an acetyl moiety to the alpha-amino group of serine 1 (S1) on histones H4 and H2A. Our previous studies linked NAA40 and its corresponding N-terminal acetylation of histone H4 (N-acH4) to colorectal cancer (CRC). However, the role of NAA40 in CRC development was not investigated.

Histone Acetyltransferases in Cancer: Guardians or Hazards?

Histone acetyltransferases (HATs) catalyzing N-epsilon-lysine or N-alpha-terminal acetylation on histone and non-histone substrates are important epigenetic regulators controlling gene expression and chromatin structure. Deregulation of these enzymes by genetic or epigenetic alterations accompanied by defects in gene transcription have been implicated in oncogenesis. Therefore, these enzymes are considered promising therapeutic targets, offering new horizons for epigenetic cancer therapy.

Functional characterisation of long intergenic non-coding RNAs through genetic interaction profiling in Saccharomyces cerevisiae.

Background: Transcriptome studies have revealed that many eukaryotic genomes are pervasively transcribed producing numerous long non-coding RNAs (lncRNAs). However, only a few lncRNAs have been ascribed a cellular role thus far, with most regulating the expression of adjacent genes. Even less lncRNAs have been annotated as essential hence implying that the majority may be functionally redundant.

Loss of Nat4 and its associated histone H4 N-terminal acetylation mediates calorie restriction-induced longevity.

Changes in histone modifications are an attractive model through which environmental signals, such as diet, could be integrated in the cell for regulating its lifespan. However, evidence linking dietary interventions with specific alterations in histone modifications that subsequently affect lifespan remains elusive. We show here that deletion of histone N-alpha-terminal acetyltransferase Nat4 and loss of its associated H4 N-terminal acetylation (N-acH4) extend yeast replicative lifespan.

Depletion of histone N-terminal-acetyltransferase Naa40 induces p53-independent apoptosis in colorectal cancer cells via the mitochondrial pathway.

Protein N-terminal acetylation is an abundant post-translational modification in eukaryotes implicated in various fundamental cellular and biochemical processes. This modification is catalysed by evolutionarily conserved N-terminal acetyltransferases (NATs) whose deregulation has been linked to cancer development and thus, are emerging as useful diagnostic and therapeutic targets. Naa40 is a highly selective NAT that acetylates the amino-termini of histones H4 and H2A and acts as a sensor of cell growth in yeast.

N-alpha-terminal acetylation of histone H4 regulates arginine methylation and ribosomal DNA silencing.

Post-translational modifications of histones play a key role in DNA-based processes, like transcription, by modulating chromatin structure. N-terminal acetylation is unique among the numerous histone modifications because it is deposited on the N-alpha amino group of the first residue instead of the side-chain of amino acids. The function of this modification and its interplay with other internal histone marks has not been previously addressed.