Review articlePost-translational modifications talk and crosstalk to class IIa histone deacetylases
Graphical abstract
Introduction
The cellular epigenome is primarily regulated by a set of writer, reader and eraser enzymes, specifically modifying histone tails and other regions of chromatin. Writers add functional moieties to histone peptide sidechains and include methyltransferases, which add methyl groups to lysines, phosphotransferases, adding phosphates and histone acetyltransferases (HATs), adding acetyl groups. Opposing the writers, erasers include demethyltransferases, phosphatases and histone deacetylases (HDACs), which remove histone or chromatin modifications. Although histone post-translational modifications (PTM) can affect genomic accessibility by altering DNA-histone interactions, epigenomic PTMs can also regulate the binding of nuclear proteins, or “readers,” that recognise and bind to these molecular features. Their binding can then recruit various different enzymes involved in processes such as DNA recombination, repair and replication [1]. Interactions between writers and readers can coordinate their activity and accessibility to their substrates by binding to specific regions of the epigenome. In addition to the poorly-understood interactions between writers, readers and erasers, these enzymes are themselves subject to various different PTMs, adding another layer of regulation. This also allows to dynamically integrate epigenetic marks according to intra-or extracellular signals. This review focuses on class IIa HDACs as particularly responsive to various PTMs to modulate cell growth, differentiation and survival.
HDACs can be divided into four different classes (I-IV), with class II further subdivided into sub-classes IIa and IIb; sub-class IIa comprises of HDAC4, HDAC5, HDAC7 and HDAC9 and class IIb with HDAC6 and HDAC10 [2]. As their name implies, HDACs are erasers that deacetylate histones, typically leading to heterochromatin formation and thus repression of adjacent genes. However, the class IIb HDAC10 and class IV HDAC11 also de-acetylate polyamines and fatty acids respectively [3,4]. However, the catalytic Y976 is not present in class IIa HDACs and the position is occupied by a histidine, strongly reducing the catalytic activity in the nucleus compared to the other HDAC classes [5]. Due to their reduced catalytic activity, class IIa HDACs are considered readers rather than erasers, recognising acetyl-lysins such as acetylated histone H3 lysine 27 and serving as scaffolds for other histone modifying enzymes such as HDAC3 and SMRT/N-COR to form a co-repressor complex [6]. Besides the reduced enzymatic activity, class IIa HDACs possess unique regulatory elements that make them more suitable for dynamically regulating epigenetic markers than HDACs from other classes, as highlighted in Fig. 1.
In contrast to class I HDACs that only have a nuclear localisation signal (NLS) or class IIb HDAC6 and HDAC10, that have a strong nuclear export signal (NES), so they predominantly localize in the cytosol, class IIa HDACs possess both, a N-terminal NLS and a C-terminal NES allowing dynamic shuttling between the cytosol and nucleus [2]. The nuclear-cytosolic shuttling is facilitated through the exportin and importin-dependent transport across the nuclear pore and is regulated via extensive phosphorylation of multiple serines [7]. To accomplish this compartmental localization, regulatory serines are distributed across multiple peptide domains of class IIa HDACs. These regions are targeted by kinases and phosphatases such as Ca2+/calmodulin-dependent protein kinase (CaMK), protein kinase A (PKA), serine/threonine-protein kinas (SIK1), protein kinase D (PKD), protein phosphatase 2 A (PP2A) and protein phosphatase 1 (PP1) [8]. Additionally, class IIa HDACs possess an N-terminal motif that permits binding (and repression) of the myocyte enhancer factor-2 (MEF2), a transcription factor that promotes myocyte differentiation and hypertrophic gene expression [9]. As the catalytic activity of HDAC4 is relatively low, the repression of MEF2-target genes is attributed to the HDAC4 dependent recruitment of classI HDACs and the SMRT/NCoR complex [6]. However, a deacetylase-independent mechanism also exists by which HDAC4 might repress MEF2 transcriptional activity. Accordingly, HDAC4 mediates the sumoylation of MEF2 at the same lysine residue that is targeted by MEF2 co-activator [10].
The importance of class IIa HDAC-dependent gene regulation is highlighted by a myriad of in vivo studies using global knock-out (KO) models of HDAC4, HDAC5, HDAC9 and HDAC7, all of which result in pre-mature death and significant growth defects [11,12]. HDAC4, 5 and 9 are primarily expressed in the brain, heart and skeletal muscle, whereas HDAC7 is mainly expressed in endothelial cells of blood vessels but also the heart, skeletal muscle and the lung [13]. Cardiac-specific and conditional KO models, as well as targeted loss-of-function mutations in the MEF2 binding motif, have allowed investigators to characterise the role of class IIa HDACs in cardiac remodelling. The laboratory of Eric Olson has demonstrated that HDAC5 and HDAC9 play an important role in suppressing cardiac hypertrophy in response to hemodynamic overload [11,14]. Additionally, it was found that that HDAC7 is involved in endothelium-dependent regulation of cardiac remodelling as well as angiogenesis [15,16]. Although cardiac specific KO of HDAC4 did not result in a changed hypertrophic response to transverse aortic constriction (TAC), cardiomyocyte-specific KO mice displayed a cardiac “fatigue” phenotype characterised by decreased ejection-fraction, decreased heart rate and lack of increased cardiac output when subjected to running exercise [17]. Pathological stressors, which include α1-adrenergic activation via phenylephrine (PE), endothelin-1 signalling, and angiotensin-II (ANG-II), facilitate cardiac hypertrophy by promoting class IIa export from the nucleus into the cytosol, thereby leading to the de-repression of MEF2 [[18], [19], [20]].
Besides regulating cardiac output via structural remodelling of the myocardium, class IIa HDACs also regulate cellular metabolism. HDAC5 inhibits the transcription of the glucose transporters 1 and 4 (GLUT1, GLUT4), downregulating glucose uptake and potentially playing a role in the development of cardiac insulin resistance in diabetic mice [21]. Additionally HDAC4 attenuates the MEF2-dependent transcription of the nuclear receptor subfamily 4 group a member 1 (Nr4a1), downregulating glutamine-fructose-6-phosphate transaminase 2 (GFPT2) and thus lowering the shunting of glucose into the hexosamine biosynthesis pathway (HBP) [17].
Section snippets
Phosphorylation regulates class IIa cellular translocation
As described above, class IIa HDACs are highly responsive to cellular signals due to several phosphorylation sites within important regulatory sites, including the NES and NLS. Activation of kinases CaMKIIδ, PKD, SIK1 and PKA are known to regulate cardiac remodelling through serine phosphorylation on class IIa HDACs [22,23]. In particular, CaMKIIδ and PKD are highly expressed in heart failure and initiate cardiac remodelling in response to sustained α1- and β1-adrenergic signalling via HDAC4
Summary
The known regulation of class IIa HDACs by PTMs offers a glimpse into the diverse mechanisms that regulate cardiac gene expression. Accordingly, modifications that prevent the nuclear export of HDAC4 or increase the binding to MEF2, such as O-GlcNAcylation or proteolytic cleavage to form HDAC4-NT during diabetic cardiomyopathy can be cardioprotective [17,89]. Consequently, modulating the phosphorylation status of class IIa HDACs can either lead to increased nuclear export and promote
Declaration of Competing Interest
J.B. is cofounder of Artemis Bio and collaborates with the Lead Discovery Center Dortmund and Novo Nordisk to develop ‘CaMKII-directed inhibitors’.
Acknowledgments
J.B. was supported by the DZHK (Deutsches Zentrum für Herz-Kreislauf-Forschung - German Centre for Cardiovascular Research) and by the BMBF (German Ministry of Education and Research).
References (115)
- et al.
Recent advances in class IIa histone deacetylases research
Bioorg. Med. Chem.
(2019) - et al.
Enzymatic activity associated with class II HDACs is dependent on a multiprotein complex containing HDAC3 and SMRT/N-CoR
Mol. Cell
(2002) - et al.
Histone deacetylase 4 controls chondrocyte hypertrophy during skeletogenesis
Cell
(2004) - et al.
Class II histone deacetylases act as signal-responsive repressors of cardiac hypertrophy
Cell
(2002) - et al.
Histone deacetylase 7 maintains vascular integrity by repressing matrix metalloproteinase 10
Cell
(2006) - et al.
Suppression of HDAC nuclear export and cardiomyocyte hypertrophy by novel irreversible inhibitors of CRM1
Biochim. Biophys. Acta
(2009) - et al.
A redox-dependent pathway for regulating class II HDACs and cardiac hypertrophy
Cell
(2008) - et al.
Histone deacetylase (HDAC) inhibition improves myocardial function and prevents cardiac remodeling in diabetic mice
Cardiovasc. Diabetol.
(2015) - et al.
Cyclic AMP represses pathological MEF2 activation by myocyte-specific hypo-phosphorylation of HDAC5
J. Mol. Cell. Cardiol.
(2020) - et al.
Histone deacetylase 5 limits cocaine reward through cAMP-induced nuclear import
Neuron
(2012)