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The many lives of KATs — detectors, integrators and modulators of the cellular environment

Abstract

Research over the past three decades has firmly established lysine acetyltransferases (KATs) as central players in regulating transcription. Recent advances in genomic sequencing, metabolomics, animal models and mass spectrometry technologies have uncovered unexpected new roles for KATs at the nexus between the environment and transcriptional regulation. Thousands of reversible acetylation sites have been mapped in the proteome that respond dynamically to the cellular milieu and maintain major processes such as metabolism, autophagy and stress response. Concurrently, researchers are continuously uncovering how deregulation of KAT activity drives disease, including cancer and developmental syndromes characterized by severe intellectual disability. These novel findings are reshaping our view of KATs away from mere modulators of chromatin to detectors of the cellular environment and integrators of diverse signalling pathways with the ability to modify cellular phenotype.

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Fig. 1: Mammalian KAT complexes.
Fig. 2: Transcriptional regulation by KAT complexes at chromatin.
Fig. 3: Acetylation as a means of cellular communication.
Fig. 4: Phenotypic abnormalities in KAT-associated developmental syndromes.

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Acknowledgements

The authors thank K. Lam, M. Shvedunova and S. Guhathakurta for their critical reading of the manuscript. The authors apologize to their colleagues whose work could not be cited here owing to space and topic constraints. B.N.S. acknowledges an Alexander von Humboldt fellowship. This work was supported by CRC 992, CRC 746 and CRC 1140 awarded to A.A.

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Glossary

Chromatin

A combination of DNA, RNA and protein that packages DNA into a compact and well-organized higher structure.

Enhancer

Genomic element, varying from a few base pairs to many kilobases in size, that serves as the major binding site of transcription factors and acts in cis to promote the transcription of associated gene loci.

Promoter

Genomic sequence commonly located just 5′ of the transcriptional start sites where the transcription apparatus assembles before activation of transcription.

Nucleosomes

Most basic units of chromatin. Each nucleosome possesses ~146 bp of DNA wrapped around a histone octamer (two each of H2A, H2B, H3 and H4).

Bromodomain

Protein domain of ~110 amino acids in length that recognizes acetylated ε-lysine residues.

Cryptic transcription

Transcription originating from unannotated transcription start sites that can occur in both intragenic and intergenic regions.

Chromosome conformation capture

Molecular biology technique that allows physical contacts between specific DNA fragments to be mapped. This technique can also be coupled to deep sequencing to map chromatin interactions throughout the genome.

Chromatin immunoprecipitation

(ChIP). Technique that allows detection of DNA fragments associated with a specific protein of interest.

Enhancer RNAs

(eRNAs). RNAs produced from the transcription of genomic enhancer elements.

Chromodomain

An ~50 amino acid protein domain that generally recognizes methylated lysines.

PHD fingers

Protein domain, generally 50–80 amino acids in length, that binds to post-translationally modified lysine residues.

Gastrulation

Developmental phase during early embryogenesis in which the three major embryonic layers (endoderm, ectoderm and mesoderm) as well as the anterior–posterior embryo axis are specified.

Podocytes

Terminally differentiated cells found in the kidney glomerulus that form part of the filtration barrier between blood and urine.

Tricarboxylic acid

(TCA). The TCA cycle, also known as the citric acid cycle or Krebs cycle, is a set of mitochondrial chemical reactions that convert energy stored in acetyl-CoA to form energy intermediates such as NADH. These intermediates are used to generate ATP.

Hippocampus

Brain area essential for laying down long-term memories. It is located below the cerebral cortex in the temporal lobe.

Morphogen

Extracellular signalling molecules, normally present during embryonic development, with the ability to induce cell fate.

Diencephalon

The most caudal part of the developing forebrain that gives rise to the hypothalamus and thalamus.

Corpus callosum

Set of ~250 million neuron projections (axons) that span and allow communication between the left and right sides of the brain.

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Sheikh, B.N., Akhtar, A. The many lives of KATs — detectors, integrators and modulators of the cellular environment. Nat Rev Genet 20, 7–23 (2019). https://doi.org/10.1038/s41576-018-0072-4

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