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Emerging Trends for H1 Variant-Specific Functions

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Emerging Trends for H1 Variant-Specific Functions Downloaded from genesdev.cshlp.org on October 1, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW The missing linker: emerging trends for H1 variant-specific functions Laura Prendergast1,2 and Danny Reinberg1,2 1Howard Hughes Medical Institute, New York University Langone Health, New York, New York 10016, USA; 2Department of Biochemistry and Molecular Pharmacology, New York University Langone Medical School, New York, New York 10016, USA Major advances in the chromatin and epigenetics fields In the 46 yr that have passed since this discovery, we as have uncovered the importance of core histones, histone a field have fixated on the nucleosome structure and right- variants and their post-translational modifications ly so. We have dissected most of its intricacies and now (PTMs) in modulating chromatin structure. However, an have a fuller understanding of core histones and how their acutely understudied related feature of chromatin struc- variants and post-translational modifications (PTMs) af- ture is the role of linker histone H1. Previous assumptions fect chromatin structure and gene expression. We have of the functional redundancy of the 11 nonallelic H1 var- evolved into many subfields, such as those focusing on iants are contrasted by their strong evolutionary conserva- the chromatin remodeling enzymes that can alter the tion, variability in their potential PTMs, and increased structure of the nucleosome, the DNA contacts, the spac- reports of their disparate functions, sub-nuclear localiza- ing between nucleosomes, histone-modifying complexes tions and unique expression patterns in different cell that change histone biochemistry, and the histone chaper- types. The commonly accepted notion that histone H1 ones that assemble and disassemble the nucleosome. functions solely in chromatin compaction and transcrip- However, one major chromatin component considered tion repression is now being challenged by work from as being essential for the formation of heterochromatin multiple groups. These studies highlight histone H1 vari- has received little attention: the family of linker histones ants as underappreciated facets of chromatin dynamics (H1). that function independently in various chromatin-based Our intent in this review is to emphasize the likelihood processes. In this review, we present notable findings in- that the H1 family of variants may also be key to under- volving the individual somatic H1 variants of which there standing several fundamental processes in chromatin are seven, underscoring their particular contributions to biology and to highlight key aspects of this frequently distinctly significant chromatin-related processes. overlooked cadre of participants in chromatin biology. Here, we discuss the proposed functions of human and mouse somatic H1 variants. The rate of discovery in the field of chromatin biology has been remarkable over the last few decades. This pro- gress is considerable given that less than a century ago, The somatic H1 variants: what is known and what is in 1928, Emil Heitz first coined the terms euchromatin unclear? and heterochromatin, describing the simple concepts of light versus dark staining patterns of chromosomes, re- Eleven H1 variants have been described in humans and spectively (Heitz 1928). No one understood how chromo- mice. This group includes four germline-specific variants: somes adopted these different structures or what three testis-specific (H1t, H1T2, and HILS1) and one oo- molecules were involved. It was not until 1974 that Olins cyte-specific (H1oo). The scope of this review will focus and Olins (1974) first observed the nucleosomes as “beads on the seven somatic (non-germline-specific) variants: on a string” via electron microscopy. This structure, DNA H1.1-H1.5, H1.0, and H1x. Here we use the human no- packaged tightly around a core of histone proteins, was menclature to avoid confusion (Table 1). Like histones proposed by Roger Kornberg (1974). A few months later, composing the nucleosome, the variants can be further Pierre Chambon (Oudet et al. 1975) termed this repeating subdivided into DNA replication-dependent variants unit of chromatin the “nucleosome” and provided both vi- (H1.1–H1.5), which are mainly expressed in S-phase and sual and biochemical evidence supporting the model pro- replication-independent variants (H1x and H1.0). posed by Kornberg (1974). © 2021 Prendergast and Reinberg This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the [Keywords: chromatin; H1; histone; histone variant; linker histone] full-issue publication date (see http://genesdev.cshlp.org/site/misc/ Corresponding author: [email protected] terms.xhtml). After six months, it is available under a Creative Commons Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.344531. License (Attribution-NonCommercial 4.0 International), as described at 120. http://creativecommons.org/licenses/by-nc/4.0/. 40 GENES & DEVELOPMENT 35:40–58 Published by Cold Spring Harbor Laboratory Press; ISSN 0890-9369/21; www.genesdev.org Downloaded from genesdev.cshlp.org on October 1, 2021 - Published by Cold Spring Harbor Laboratory Press Emerging trends for H1 variant-specific functions Evolutionary conservation of H1 variants (Croston et al. 1991; Laybourn and Kadonaga 1991). How- ever, more recent studies show that this is not always the Comparison of the mouse and human H1 gene sequences case. In fact, some H1 variants are associated with active reveals that each variant is more similar to its ortholog gene expression, suggesting that the presence of H1 does than other intra-species variants (Fig. 1A–C; Drabent not always result in chromatin structures that are imper- et al. 1995), suggesting that these variants have been evo- missible to transcription (Table 3, below; Fan et al. 2005; lutionarily conserved. The human replication-dependent Sancho et al. 2008; Zheng et al. 2010; Kamieniarz et al. H1 variants do exhibit considerable sequence similarity 2012; Izzo et al. 2013; Mayor et al. 2015). to each other (Fig. 1B). H1.3 and H1.4 are the most similar to the replication-dependent variants with an 86% over- lap, whereas, H1.1 and H1.5 are the most divergent with Variability and discrepancies in H1 variant interaction only a 66.4% overlap (Drabent et al. 1995; Pan and Fan with chromatin 2016). In contrast, replication-independent variants There are still many gaps in our understanding of H1-de- show very little sequence similarity to the other somatic pendent chromatin compaction. The following evidence variants, and even less sequence similarity to each other highlights how important it is for future studies to clearly (Fig. 1B,C; Drabent et al. 1995; Pan and Fan 2016). distinguish between H1 variants when studying chroma- tin dynamics. First, the H1 variants display a broad range H1 structure and general function of both affinity for and ability to compact chromatin (Ta- ble 2; Clausell et al. 2009; Öberg et al. 2012; Perišićet al. The somatic H1 variants in mammals all have a similar 2019). The H1 C-terminal tail, which is also important for structure, consisting of a highly conserved central globu- chromatin compaction and organization (Bednar et al. lar domain and less conserved N- and C-terminal tails. 2017; Turner et al. 2018), varies in sequence and length be- A generally recognized function of linker histones is their tween the variants, likely explaining their differences. Ac- binding to and facilitating the folding of chromatin into a cordingly, two weak compactors of chromatin, H1.1 and more compact form. H1 accomplishes compaction via its H1.2, both have a shorter C-terminal tail compared with globular domain that binds to DNA entry/exit points of those of the other H1 variants (Clausell et al. 2009). It the nucleosome at the dyad axis (center of the nucleoso- has also been reported that the PTMs associated with mal DNA), forming a structure called the chromatosome the H1 variants can alter their affinity for chromatin and (Fig. 2). Unfortunately, as much of the N- and C-terminal their compacting ability (Perišićet al. 2019); e.g., when tails of H1 are intrinsically disordered, resolving the com- acetylated at lysine 34, H1.4 has a decreased affinity for plete structure of H1 bound to the nucleosome by X-ray chromatin (Table 4, below; Kamieniarz et al. 2012). crystallography is a challenge. Very recently, using cut- Second, whether H1 binding to the nucleosome is equi- ting edge cryo-EM techniques, the structure of avian H1 distant to each DNA entry/exit point (on-dyad) or closer (H5) bound to a dedocanucleosome has been determined to one DNA entry/exit point (off-dyad) (Fig. 2) has been de- at 3.6 Å resolution, revealing the atomic structure of an al- bated in the field; models for each have been proposed most full-length linker histone H5 (G Li and P Zhu, pers. (Song et al. 2014; Zhou et al. 2015; Bednar et al. 2017). comm.). It has also come to our attention that cryo-EM Structural data for H1.5 and H1.0 binding supports the structures of chromatosomes prepared with full-length on-dyad model (Bednar et al. 2017). However, many in H1x, H1.0, and H1.4 variants have been completed and the field have accepted the off-dyad model based on will be available very soon (Zhou et al. 2020). cryo-EM data using H1.4 (Song et al. 2014). The mecha- After the discovery of this effect of H1 on chromatin nism by which H1 binding influences the compaction structure and the transcriptionally repressed chromatin and structure of chromatin is still unclear (recently re- states inherently incurred upon H1 incorporation, H1 viewed [Öztürk et al. 2020]). The Bai laboratory (Zhou was proposed as being a general repressor of transcription et al. 2015) proposed that H1 binding on-dyad would lead to more compact chromatin than binding off-dyad us- ing ultracentrifugation sedimentation coefficients; how- Table 1.
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