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Kumar, A.;  Maurya, P.;  Hayes, J.J. PTMs and Mutations of Human Linker Histone Subtypes. Encyclopedia. Available online: https://encyclopedia.pub/entry/40376 (accessed on 17 July 2025).
Kumar A,  Maurya P,  Hayes JJ. PTMs and Mutations of Human Linker Histone Subtypes. Encyclopedia. Available at: https://encyclopedia.pub/entry/40376. Accessed July 17, 2025.
Kumar, Ashok, Preeti Maurya, Jeffrey J. Hayes. "PTMs and Mutations of Human Linker Histone Subtypes" Encyclopedia, https://encyclopedia.pub/entry/40376 (accessed July 17, 2025).
Kumar, A.,  Maurya, P., & Hayes, J.J. (2023, January 18). PTMs and Mutations of Human Linker Histone Subtypes. In Encyclopedia. https://encyclopedia.pub/entry/40376
Kumar, Ashok, et al. "PTMs and Mutations of Human Linker Histone Subtypes." Encyclopedia. Web. 18 January, 2023.
PTMs and Mutations of Human Linker Histone Subtypes
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This entry is adapted from the peer-reviewed paper 10.3390/ijms24021463

Linker histones (LH) are a critical component of chromatin in addition to the canonical histones (H2A, H2B, H3, and H4). In humans, 11 subtypes (7 somatic and 4 germinal) of linker histones have been identified, and their diverse cellular functions in chromatin structure, DNA replication, DNA repair, transcription, and apoptosis have been explored, especially for the somatic subtypes. Delineating the unique role of human linker histone (hLH) and their subtypes is highly tedious given their high homology and overlapping expression patterns. However, advancements in mass spectrometry combined with HPLC have helped in identifying the post-translational modifications (PTMs) found on the different LH subtypes. However, while a number of PTMs have been identified and their potential nuclear and non-nuclear functions explored in cellular processes, there are very few studies delineating the direct relevance of these PTMs in diseases. In addition, whole-genome sequencing of clinical samples from cancer patients and individuals afflicted with Rahman syndrome have identified high-frequency mutations and therefore broadened the perspective of the linker histone mutations in diseases.

linker histone post-translational modification H1 subtypes

1. Introduction

The eukaryotic nuclear DNA is packaged inside the nucleus in a beads-on-a-string structure by wrapping ~147 bp around the core histone (H2A, H2B, H3 and H4) octamer to form nucleosome cores, connecting the cores by stretches of linker DNA. Linker histones (LH) bind at the linker entry and exit site on the nucleosome to stabilize and condense the chromatin to form higher-order chromatin fiber [1][2][3]. The condensation and decondensation of the chromatin by LH regulates the dynamic function of cells such as cell cycle, replication, DNA repair, RNA turnover, transcription and development [4][5][6][7][8]. The LH functional diversity thought to be augmented further in higher eukaryotes because of simultaneous expression of multiple variants (11 subtypes): seven somatic (H1.0, H1.1–H1.5 and H1.10) and four germ cells (H1T, H1T2, HILS1 and H1OO). The sequence variations in the subtypes indicates conserved distinct structural and functional properties of these subtypes in chromatin arrangement and cellular processes [9]. Since the discovery of H1s, numerous studies have been performed to understand the redundant and non-redundant biological roles of H1s in cellular processes. For example, deletion of one or two subtypes is compensated by the overexpression of others, while the deletion of three subtypes is found to be embryonically lethal in mice [10][11][12][13]. Furthermore, a diverse array of post-translational modifications (PTMs) in H1s adds to the potential complexity of LH diverse functions, but the functions of most LH PTMs are poorly understood [14].
Epigenetics play a crucial role in regulating the physiological processes of the cell and are influenced by environmental stimuli. Epigenetic modifications, in general, are reversible phenomena and have been associated with many pathologies, including several cancers, and therefore, the processes regulating these modifications have become drug targets [15]. As per the histone code hypothesis, the different modifications of histone acting alone or simultaneously have distinct downstream functions [16][17][18]. Advancements in mass spectroscopy have revolutionized the precise identification of PTMs in proteins and have led to the identification of a number of PTMs in LH subtypes, compared to the cumbersome methodology of radioactivity and antibody-based detection. The PTMs of canonical histones are identified unambiguously and have been extensively studied, while the PTMs of LHs are beginning to be identified in initial studies, in nine out of the eleven mammalian subtypes [19]. LHs have a net basic charge, and their CTD is rich in basic charged residues, especially lysine, with few arginine residues, which promotes chromatin condensation and functions in diverse cellular processes such as DNA damage, transcription and cellular differentiation [20][21][22][23][24][25]. In addition to PTMs, cancer genome sequencing studies have highlighted mutations in a number of the proteins involved in regulating epigenetic marks, as well as in histone proteins themselves, indicating the importance of these marks in disease [26][27][28].

2. Human Linker Histone and Its Subtypes

LHs in higher eukaryotes have a tripartite structure, with a trypsin-resistant central globular domain (GD) (~80 residues) flanked by unstructured and protease-sensitive N-terminal domain (NTD) (~25–35 amino acids), and C-terminal domain (CTD) (~100 residues) (Figure 1A). The CTD possesses more than 40 lysine residues, thus making it a highly positively charged segment of LH. Indeed, while the structured GD is responsible for structure-specific recognition and binding to the nucleosome surface, the CTD stabilizes binding via interaction with the linker DNA segments (Figure 1B), as well as stabilizing higher order chromatin structure by neutralizing the densely packed negative charge of DNA [1][2][29][30][31][32]. The wing helix domain (WHD) of the LH interacts with the nucleosome over the dyad axis and with the first ~10 bp of each linker DNA in a symmetric or asymmetric fashion suggested to be based on chromatin dynamic events [33][34][35]. Linker histones are evolutionarily more diverse than the canonical histones, but the GD is conserved through evolution in plants, fungi and animals and exhibits the greatest sequence conservation, while the NTD and CTD exhibit greater sequence variation [36]. Initially, few LH subtypes had been reported [37]; however, with extensive research, multiple subtypes of LHs have been reported across different species: e.g., Gallus gallus with 7, Drosophila melanogaster has one somatic and one embryonic subtype, Saccharomyces cerevisiae has one, and mammals have 11 subtypes. Interestingly, LH subtypes have more similarity between species when compared within the species (Figure 1C) [36][38]. LHs are also categorized based on their expression patterns in tissues. For example, humans have two classes of somatic subtypes: five that are ubiquitously expressed in a replication dependent fashion (H1.1-H1.5), and two that are expressed in a replication independent, and found mainly in terminally differentiated cells (H1.0 and H1x). Humans also have germ cell-specific LHs, with one oocyte specific (H1oo), and three testis specific (H1T/H1.6, H1T2, and HILS1). These subtypes are distributed over a wide variety of genomic locations, with H1.1, H1.2, H1.3, H1.4, H1.5, H1.0, H1X/H1.10, H1T/H1.6, H1T2/H1.7, H1LS1/H1.9, H1oo/H1.8 found on chromosomes 6p21.3, 6p21.3, 6p21.3, 6p21.3, 6p22.1, 22q13.1, 3q21.3, 6p21.3, 12q13.1, 17q21.33, 3q22.1, respectively [39][40][41]. Although subtypes within the species show higher similarity in their GD sequence, they possess heterogeneity among amino and carboxyl terminal domain sequences. In addition, there have been a number of PTMs reported in these domains. Overall, the heterogeneity in their NDT, CTD and PTMs can be considered for diversity in LH functions.
Ijms 24 01463 g001
Figure 1. (A) General structure of linker histone with central globular domain (red), unstructured N-terminal domain (dotted red), and long C-terminal domain (dotted red). (B) CryoEM structure of the nucleosome with linker histone H1.4 prepared by PyMol using PDB ID: 7k5y. The central portion is octamer of histone (green), Linker histone H1.4 (red). (C) Phylogeny tree of linker histone from Saccharomyces cerevisiae (Sc), Homo sapiens (Hs), Drosophila melanogaster (Dm), Gallus (Gg).

3. Post-Translational Modifications of Human Linker Histones

LHs are an essential component of chromatin and play diverse roles in cellular processes. The functional diversity of LHs are because of the heterogeneity in their unstructured N and C-terminal domains and the PTMs in these domains. The PTMs of canonical histones were first identified in 1960s and extensively studied, while the first PTM of LH was identified almost a decade later, within Physarum polycephalum H1 using radioactive 32P labelling followed by electrophoresis and, successively, from different species Drosophila melanogaster, chicken erythrocytes Chinese hamster ovary cells, and mammalian cell lines [19][42][43][44][45][46]. However, because of 32P labelling, difficulties in separation of the linker histone subtypes, the lack of subtype-specific antibodies, and the lack of a highly sensitive method to detect the PTMs in low amounts of proteins, such LH PTMs studies were limited. The introduction of mass spectroscopy, trypsin digestion and separation of the peptides by HPLC followed by amino acid analysis using the Edman degradation helped in the identification of the phosphorylated LH. However, the exact site of phosphorylation in LH was elusive for many subtypes until advancements in PTMs identification methodologies. The technical limitation of retention of highly positive charge (basic) peptides on C18 resin (capillary column) were overcome by using a propionylating reagent which removes the charge from unmodified and monomethylated lysine residues and adds a hydrophobic propionyl group which increases the retention time of the peptide on the C18 column. In addition, the combination of high-performance liquid chromatography (HLPC), reversed-phase (RP)-HPLC, hydrophilic interaction liquid chromatography (HILIC), high-performance capillary electrophoresis (HPCE), enzymatic cleavage, amino acid sequence analysis, and linear quadrupole ion trap-Fourier-Transform Ion Cyclotron Resonance (LTQ-FT-ICR) mass spectrometry provided better coverage, high resolution and mass accuracy, leading to the identification of LH subtypes [47]. Furthermore, LH subtype separation and additional PTMs (ubiquitination and formylation) were detected with high confidence from HeLa and MCF7 cell lines using liquid chromatography (LC) connected to an LTQ-Orbitrap mass spectrometer having a nanoelectrospray ion source [48]. Starkova et al. employed Matrix-activated laser desorption/ionization Fourier-transform ion cyclotron resonance mass-spectroscopy (MALDIFT-ICR-MS) coupled with acetic acid–urea polyacrylamide gel electrophoresis (AU-PAGE), second dimension SDS-PAGE and trypsin digestion, which led to the separation of LH subtypes (H1.0, H1.X, H1.1, H1.2, H1.3, H1.4 and H1.5) from human K562 cell line from tissue samples of mouse and calf thymi to separate the LH subtypes (H1.1, H1.2, H1.3, H1.4) and identification of novel PTMs at meK75-hH1.3, acK26-hH1.4, acK26-hH1.3 and acK17-hH1.1 [49].
The NTD and CTD of many LH subtypes contains multiple cyclin-dependent kinase (CDK) motifs ((S/T)PXZ, where X is any amino acid and Z is a basic amino acid), and in vivo data suggests that these CDK motifs undergo site-specific cell-cycle-dependent phosphorylation [20][50]. Mass spectroscopy and biochemical studies established that basic amino acids of LH are primarily responsible for its interaction with chromatin and their stabilization. The LH PTMs such as phosphorylation, acetylation, formylation, propionylation, and crotonylation result in reduction of the positive charge of LH, which impacts the chromatin stability and furthermore the compact state of the chromatin, while methylation tends to be associated more repressed chromatin state [20][49][50][51]. An overview of LH PTMs in cellular function is shown in Figure 2. The most commonly identified human LH PTMs are phosphorylation, acetylation, and methylation, with less extents of formylation, citrullination, sumoylation, and lysine β-hydroxybutyrylation, as identified by mass spectrometry of proteins from different cell lines and clinical samples. 
Ijms 24 01463 g002 550
Figure 2. A general overview of involvement of linker histone PTMs in cellular processes; Linker histone PTMs (phosphrorylation (P), acetylation (Ac), methylation (Me), and citrulation (Ctr) have critical involvement in the normal physiological and disease states.

4. Modulators of Linker Histone Post-Translational Modifications

The emerging role of linker histone PTMs in cellular processes generates interest in how these PTMs are modulated. Phosphorylation is one of the extensively studied PTMs of LH and has been found to be cell cycle dependent with the lowest level in G1, reaching to maximal level in metaphase [47][52]. It has been found that human H1.4S27, H1.4S35 and H1.5T10 are phosphorylated by Aurora B kinase, protein kinase A, and glycogen synthase kinase-3, respectively, and they are predominant in the mitotic stage, while human H1.5S17, in phosphorylated form, is observed in early G1 phase, and H1.5S172 and H1.5S188 phosphorylation occurs in S phase. Although protein phosphatase 1 (PP1) has been suggested as a phosphatase for reversing the LH phosphorylation, the protein kinase inhibitor staurosporine has been reported to specifically dephosphorylate H1.5T10 compared to H1.5S17, H1.5S172 and H1.5S188, and prolonged dexamethasone exposure (48 h) in Mouse 1471.1 cells reduces the phosphorylation level of H1.3 and H1.4 [14][21][22][52][53][54]. In addition, positive transcription elongation factor b (P-TEFb), the complex of cyclin T1 and CDK9 reported to phosphorylate the LH and inhibition of P-TEFb by RNAi, flavopiridol, or dominant negative CDK9 expression results in a reduction in phosphorylation. Furthermore, H1.4K26 is methylated by either Ezh2 or G9a, and can be demethylated by members of the Jumonji domain 2 (JMJD2) subfamily of demethylases, similar to an analogous sequence in the N-terminal tail domain of H3. However, methylation of H1.2 at K187 is mediated by G9a in association with its binding partner Glp1 and H1.2K187 methylation is non reversible by the JMJD2. Acetylation of H1.4K34 is associated with GCN5 while H1.4K34, and H1.4K26 gets deacetylated by SIRT1. The writer of H1.4K26 acetylation still need to be explored [14]. In DNA damage condition, H1.2 S188 PARylation is mediated by PARP1, which poly-ADP-ribosylate it and in turn impacts the association with chromatin [55]. Peptidylarginine deiminase 4 (PADI4) has been suggested to mediate the citrullination at R54 of LH subtypes (H1.2, H1.3 and H1.4) [25]. The understanding of the modulators of human linker histone (hLH) PTMs can help in finding novel small molecule inhibitors or activators such as dexamethasone, flavopiridol, and staurosporine.

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Subjects: Biochemistry & Molecular Biology
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