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Most cells in the human body (except germ cells) are diploid and contain approximately 6 billion base pairs of DNA. Each base pair is about 0.34 nanometers long, so the total length of human diploid DNA is around 2 m. How are so long DNA molecules packaged inside microscopic nuclei? One category of particular proteins, histones, allow DNA to be folded and compacted into tiny nuclei. What exactly are histones?
In this article, we'll take a closer look at histones. We'll see what histones are, how the structure of histones supports their function, and their classification, and how histones cause diseases.
Histones were initially isolated from avian red blood cells and were described by Albrecht Kossel in 1884. Histones are abundant in basic amino acids arginine and lysine. They are alkaline and water-soluble proteins and carry positive charges that allow for their tight binding with negatively charged DNA. In eukaryotic cells, histones bind to and condense DNA into chromatin.
Histones are mainly divided into five categories according to their amino acid compositions and molecular weight, including core histones: H2A, H2B, H3, and H4, and linker histone: H1 / H5 [1]. The core histones have similar histone fold domain-containing three alpha-helices linked by two loops that allow for interaction between different dimers [2]. Two copies of each of the four core histones bind to about 147 base pairs of DNA forming nucleosomes. Besides, the unstructured N-terminal tails of histones extend through the DNA gyres and into the space surrounding the nucleosomes, providing sites for multiple PTMs [3]. Linker histone H1 associates with the linker region of DNA between two nucleosomes, facilitating the construction of numerous nucleosomes into higher-order chromatin structures. H1 varies greatly between species. As the variant of H1, H5 is the major linker histone in avian erythrocytes.
| Super family | Family | Location and Function | Subfamily | Members |
|---|---|---|---|---|
| Linker | H1 | On the connecting line; bind to nucleosomes and linker-DNA in the chromatin fiber | H1F | H1F0, H1FNT, H1FOO, H1FX |
| H1H1 | HIST1H1A, HIST1H1B, HIST1H1C, HIST1H1D, HIST1H1E, HIST1H1T | |||
| Core | H2A | Core particles; take part in the formation of nucleosomes | H2AF | H2AFB1, H2AFB2, H2AFB3, H2AFJ, H2AFV, H2AFX, H2AFY, H2AFY2, H2AFZ |
| H2A1 | HIST1H2AA, HIST1H2AB, HIST1H2AC, HIST1H2AD, HIST1H2AE, HIST1H2AG, HIST1H2AI,HIST1H2AJ, HIST1H2AK, HIST1H2AL, HIST1H2AM | |||
| H2A2 | HIST2H2AA3, HIST2H2AC | |||
| H2B | Core particles; take part in the formation of nucleosomes | H2BF | H2BFM, H2BFS, H2BFWT | |
| H2B1 | HIST1H2BA, HIST1H2BB, HIST1H2BC, HIST1H2BD, HIST1H2BE, HIST1H2BF, HIST1H2BG,HIST1H2BH, HIST1H2BI, HIST1H2BJ, HIST1H2BK, HIST1H2BL, HIST1H2BM, HIST1H2BN, HIST1H2BO | |||
| H2B2 | HIST2H2BE | |||
| H3 | Core particles; take part in the formation of nucleosomes | H3A1 | HIST1H3A, HIST1H3B, HIST1H3C, HIST1H3D, HIST1H3E, HIST1H3F, HIST1H3G, HIST1H3H, HIST1H3I, HIST1H3J | |
| H3A2 | HIST2H3C | |||
| H3A3 | HIST3H3 | |||
| H4 | Core particles; take part in the formation of nucleosomes | H41 | HIST1H4A, HIST1H4B, HIST1H4C, HIST1H4D, HIST1H4E, HIST1H4F, HIST1H4G, HIST1H4H, HIST1H4I, HIST1H4J, HIST1H4K, HIST1H4L | |
| H44 | HIST4H4 |
Table: Histone family members
In the nucleus, histones primarily function to compact DNA strands and impact chromatin regulation [4]. Histone also subjected to a number of post-modifications (PTMs), including acetylation, methylation, ubiquitylation, and phosphorylation. Epigenetic histone modification pathways play a key role in the modulation of nucleosome dynamics [3] and multiple DNA-associated processes such as transcription [5][6], replication [7][8], and repair [9]. For example, histone acetyltransferase-mediated acetylation of lysine in the promoter regions of histones leads to repressive heterochromatin-to-permissive euchromatin switch, increasing transcription factor binding to DNA and subsequent gene transcription and expression. Histone methyltransferase-mediated histone methylation has either positive effects or negative impacts on gene expression depending on the location and association of other protein complexes. The fact that the combination of these modifications, also known as "histone code", ultimately control gene expression [22]. At the cell surface, histones promote cell-mediated apoptosis, neurogenesis, migration, and endocytosis. Additionally, emerging studies show that histones are released into the extracellular space, where histones exert remarkable toxic or pro-inflammation activity in vivo and vitro [10] [11].
Histones are the basic structural proteins of eukaryotic chromatin. However, under stress conditions such as inflammation, infection, ischemia, and hypoxia, cells may undergo apoptosis, necrosis, or NETosis (a unique form of immune cell death caused by increased release of neutrophilic extracellular traps (NETs)), thus leading to the release of histones into the extracellular space, where histones can activate immune and inflammatory responses, initiating or aggravating tissue injury, or mediating the occurrence and development of various diseases, including sepsis, pancreatitis, peritonitis, liver injury, kidney injury, coagulation, detachment, and apoptosis.
Figure：Release and activity of histones in response to stress
The picture is cited from https://www.nature.com/articles/cddis2014337
During sepsis, pro-inflammatory factors TNF-α and IL-6 are released in large quantities, triggering the efflux of histones into extracellular space, thus resulting in endothelial dysfunction, organ failure, and death [11]. Kang R et al. showed that extracellular histone-mediated HMGB1 release in activated immune cells contributes to L-arginine-induced acute pancreatitis in HMGB1 pancreatic conditional knockout mice [12]. Extracellular histones can activate the NLRP3 inflammasome and indirectly induce cell necrosis to produce local cytokines, thus leading to peritonitis [13]. Once released, histones selectively bind to TLRs, including TLR-2, TLR-4, TLR9 to generate pro-inflammatory cytokines, which enhance inflammatory response and tissue damage in the liver [14] [15], kidney [16], lung [17], and brain. The TLR2 and TLR4 signaling pathways induced also promote platelet activation, blood coagulation, increase the level of von Willebrand factor, and accelerate the early occurrence of deep vein thrombosis [18]. Kawano H et al. revealed that histones released from damaged retinal in retinal detachment (RD) may deteriorate the condition of the subretinal microenvironment by inducing inflammation and cell death in retinal pigment epithelial (RPE) cells [19]. Histones released from NETosis have been involved in numerous autoimmune and autoinflammatory diseases such as systemic lupus, rheumatoid arthritis, and small-vessel vasculitis. Extracellular histones and histone modifications also correlate with the pathogenesis of neurological diseases, including ischemia-reperfusion injury, histone modification-mediated transcription disorders, and glial cell reactive hyperplasia. Increasing evidence indicates that histone aberrant modifications contribute to human diseases such as cancer, neurodevelopment disorders, neurodegenerative diseases, and pathogen infection [20] [21].
Studies have been demonstrated that serum histones and nucleosomes can act as indicators of various health or disease futures and may be potent biomarkers for diseases, particularly cancer. Extracellular histones also may be useful biomarkers that will improve the diagnosis, prognosis, and management of human diseases. Anti-histone-based therapeutic strategies may also be useful in treating several diseases.
References
[1] Bhasin M, Reinherz EL, et al. Recognition and classification of histones using support vector machine [J]. J Comput Biol. 2006 Jan-Feb;13(1):102-12.
[2] Mariño-Ramírez L, Kann MG, et al. Histone structure and nucleosome stability [J]. Expert Review of Proteomics. 2005, 2 (5): 719–29.
[3] Kouzarides T. Chromatin modifications and their function [J]. Cell 2007, 128, 693–705.
[4] Campos EI, Reinberg D. Histones: annotating chromatin [J]. Annu Rev Genet 2009; 43: 559–599.
[5] Shilatifard A. Chromatin modifications by methylation and ubiquitination: implications in the regulation of gene expression [J]. Annu. Rev. Biochem 2006， 75, 243–269.
[6] Li B, Carey M, et al. The role of chromatin during transcription [J]. Cell 2007, 128, 707–719.
[7] Unnikrishnan A, Gafken PR, et al. Dynamic changes in histone acetylation regulate origins of DNA replication [J]. Nat. Struct. Mol. Biol 2010, 17, 430–437.
[8] Jacob Y, Stroud H, et al. Regulation of heterochromatic DNA replication by histone H3 lysine 27 methyltransferases [J]. Nature 2010, 466, 987–991.
[9] Scully R. A histone code for DNA repair [J]. Nat. Rev. Mol. Cell. Biol 2010, 11, 164.
[10] Allam R, Kumar SV, et al. Extracellular histones in tissue injury and inflammation [J]. J Mol Med (Berl) 2014; 92: 465–472.
[11] Xu J, Zhang X, et al. Extracellular histones are major mediators of death in sepsis [J]. Nat Med 2009; 15: 1318–1321.
[12] Kang R, Zhang Q, et al. Intracellular Hmgb1 Inhibits Inflammatory Nucleosome Release and Limits Acute Pancreatitis in Mice [J]. Gastroenterology 2014; 146: 1097–1107.
[13] Allam, R., Darisipudi, M. N., et al. Histones trigger sterile inflammation by activating the NLRP3 inflammasome [J]. Eur. J. Immunol. 2013, 43, 3336–3342.
[14] Huang H, Evankovich J, et al. Endogenous histones function as alarmins in sterile inflammatory liver injury through Toll-like receptor 9 in mice [J]. Hepatology 2011; 54: 999–1008.
[15] Wen Z, Liu Y, et al. Circulating histones exacerbate inflammation in mice with acute liver failure [J]. J Cell Biochem 2013; 114: 2384–2391.
[16] Allam R, Scherbaum CR, et al. Histones from dying renal cells aggravate kidney injury via TLR2 and TLR4[J]. J Am Soc Nephrol 2012; 23: 1375–1388.
[17] Bosmann M, Grailer JJ, et al. Extracellular histones are essential effectors of C5aR-and C5L2-mediated tissue damage and inflammation in acute lung injury[J]. Faseb J 2013; 27: 5010–5021.
[18] Carestia A, Rivadeneyra L, et al. Functional responses and molecular mechanisms involved in histone-mediated platelet activation [J]. Thromb Haemost 2013; 110: 1035–1045.
[19] Kawano H, Ito T, et al. Toxic effects of extracellular histones and their neutralization by vitreous in retinal detachment [J] Lab Invest 2014; 94: 569–585.
[20] Bhaumik SR, Smith E, et al. Covalent modifications of histones during development and disease pathogenesis [J]. Nat Struct Mol Biol 2007; 14: 1008–1016.
[21] Portela A, Esteller M. Epigenetic modifications and human disease [J]. Nat Biotechnol 2010; 28: 1057–1068.
[22] Carlberg C., Molnár F. The Histone Code. In: Human Epigenomics. Springer, Singapore, 2018.
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