bims-meprid 2021-08-01 papers

EMBO Rep. 2021 Jul 30. e53251

Integration of transcriptional and metabolic control in macrophage activation.

Gioacchino Natoli, Francesco Pileri, Francesco Gualdrini, Serena Ghisletti.

Macrophages react to microbial and endogenous danger signals by activating a broad panel of effector and homeostatic responses. Such responses entail rapid and stimulus-specific changes in gene expression programs accompanied by extensive rewiring of metabolism, with alterations in chromatin modifications providing one layer of integration of transcriptional and metabolic regulation. A systematic and mechanistic understanding of the mutual influences between signal-induced metabolic changes and gene expression is still lacking. Here, we discuss current evidence, controversies, knowledge gaps, and future areas of investigation on how metabolic and transcriptional changes are dynamically integrated during macrophage activation. The cross-talk between metabolism and inflammatory gene expression is in part accounted for by alterations in the production, usage, and availability of metabolic intermediates that impact the macrophage epigenome. In addition, stimulus-inducible gene expression changes alter the production of inflammatory mediators, such as nitric oxide, that in turn modulate the activity of metabolic enzymes thus determining complex regulatory loops. Critical issues remain to be understood, notably whether and how metabolic rewiring can bring about gene-specific (as opposed to global) expression changes.

Keywords: epigenetics; inflammation; macrophages; metabolism; transcription

DOI: https://doi.org/10.15252/embr.202153251

Exp Hematol. 2021 Jul 21. pii: S0301-472X(21)00249-6. [Epub ahead of print]

ReviewO-GlcNAcylation: implications in normal and malignant hematopoiesis.

Hideaki Nakajima, Koichi Murakami.

Post-translational protein modification by adding O-linked β-N-acetyl-D-glucosamine (O-GlcNAc) moiety to serine or threonine residues, termed O-GlcNAcylation, is a highly dynamic process conserved throughout eukaryotes. O-GlcNAcylation is reversibly catalyzed by a single pair of enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), and it acts as a fundamental regulator for wide variety of biological processes including gene expression, cell cycle regulation, metabolism, stress response, cellular signaling, epigenetics and proteostasis. O-GlcNAcylation is regulated by various intracellular or extracellular cues such as metabolic status, nutrients availability or stress. Studies over decades have unveiled profound biological significance of this unique protein modification in normal physiology and pathological processes of diverse cell types or tissues. In hematopoiesis, recent studies have shown the essential and pleiotropic roles of O-GlcNAcylation in differentiation, proliferation and function of hematopoietic cells including T cells, B cells, myeloid progenitors and hematopoietic stem and progenitor cells. Moreover, aberrant O-GlcNAcylation is implicated in the development of hematological malignancies with dysregulated epigenetics, metabolism and gene transcription. Thus, it is now recognized that O-GlcNAcylation is one of the key regulators of normal and malignant hematopoiesis.

Keywords: O-GlcNAc; O-GlcNAc transferase; O-GlcNAcylation; OGT; O‐linked β-N-acetyl-D-glucosamine; epigenetics; hematological malignancies; hematopoiesis; hematopoietic stem cells; metabolism; post-translational modification

DOI: https://doi.org/10.1016/j.exphem.2021.07.003

J Bacteriol. 2021 Jul 26. JB0033321

Sirtuin-dependent reversible lysine acetylation controls the activity of acetyl-Coenzyme A synthetase in Campylobacter jejuni.

Victoria L Jeter, Jorge C Escalante-Semerena.

Posttranslational modifications are mechanisms for rapid control of protein function used by cells from all domains of life. Acetylation of the epsilon amino group (Nε) of an active-site lysine of the AMP-forming acetyl-CoA synthetase (Acs) enzyme is the paradigm for the posttranslational control of the activity of metabolic enzymes. In bacteria, the alluded active-site lysine of Acs enzymes can be modified by a number of different GCN5-type N-acetyltransferases (GNATs). Acs activity is lost as a result of acetylation, and restored by deacetylation. Using a heterologous host, we show that Campylobacter jejuni NCTC11168 synthesizes enzymes that control Acs function by reversible lysine acetylation (RLA). This work validates the function of gene products encoded by the cj1537c, cj1715, and cj1050c loci, namely the AMP-forming acetate:CoA ligase (CjAcs), a type IV GCN5-type lysine acetyltransferase (GNAT, hereafter CjLatA), and a NAD+-dependent (class III) sirtuin deacylase (CjCobB), respectively. To our knowledge, these are the first in vivo and in vitro data on C. jejuni enzymes that control the activity of CjAcs. IMPORTANCE This work is important because it provides the experimental evidence needed to support the assignment of function to three key enzymes, two of which control the reversible posttranslational modification of an active-site lysyl residue of the central metabolic enzyme acetyl-CoA synthetase (CjAcs). We can now generate Campylobacter jejuni mutant strains defective in these functions, so we can establish the conditions in which this mode of regulation of CjAcs is triggered in this bacterium. Such knowledge may provide new therapeutic strategies for the control of this pathogen.

DOI: https://doi.org/10.1128/JB.00333-21

Cell Rep. 2021 Jul 27. pii: S2211-1247(21)00883-4. [Epub ahead of print]36(4): 109460

Metabolically controlled histone H4K5 acylation/acetylation ratio drives BRD4 genomic distribution.

In addition to acetylation, histones are modified by a series of competing longer-chain acylations. Most of these acylation marks are enriched and co-exist with acetylation on active gene regulatory elements. Their seemingly redundant functions hinder our understanding of histone acylations' specific roles. Here, by using an acute lymphoblastic leukemia (ALL) cell model and blasts from individuals with B-precusor ALL (B-ALL), we demonstrate a role of mitochondrial activity in controlling the histone acylation/acetylation ratio, especially at histone H4 lysine 5 (H4K5). An increase in the ratio of non-acetyl acylations (crotonylation or butyrylation) over acetylation on H4K5 weakens bromodomain containing protein 4 (BRD4) bromodomain-dependent chromatin interaction and enhances BRD4 nuclear mobility and availability for binding transcription start site regions of active genes. Our data suggest that the metabolism-driven control of the histone acetylation/longer-chain acylation(s) ratio could be a common mechanism regulating the bromodomain factors' functional genomic distribution.

DOI: https://doi.org/10.1016/j.celrep.2021.109460