# HP1BP3

## Overview
HP1BP3 is a gene located on chromosome 1p36 in humans, encoding the protein heterochromatin protein 1 binding protein 3. This protein is a member of the H1 linker histone multigene family and plays a significant role in chromatin dynamics, particularly in the transition between euchromatin and heterochromatin. HP1BP3 is characterized by its tripartite structure, which includes a glutamate-rich N-terminal domain, three globular domains, and a highly basic C-terminal domain. The protein is predominantly localized in the nucleus, where it interacts with heterochromatin protein 1 (HP1) through a canonical binding motif, PQVKL, and is involved in maintaining chromatin structure and regulating gene expression. HP1BP3's function is crucial for cell cycle regulation, transcriptional regulation, and maintaining normal cellular function. Alterations in its expression or function have been linked to various clinical conditions, including cognitive decline, growth deficiencies, and cancer progression (Garfinkel2015HP1BP3; Neuner2018Knockdown; Dutta2014Profiling).

## Structure
HP1BP3 is a protein encoded by the HP1BP3 gene, located on chromosome 1p36 in humans. The protein is 553 amino acids long and is a member of the H1 linker histone multigene family, present in all vertebrates (Garfinkel2015HP1BP3). Its structure includes a glutamate-rich N-terminal domain (NTD) of 100 amino acids, followed by three globular domains (GD1, GD2, GD3), a 20 amino acid poly aspartate/glutamate tract (DE), and a highly basic 100 amino acid long C-terminal domain (CTD) (Garfinkel2015HP1BP3). The CTD's amino acid composition is similar to the CTDs of gonadal subtypes H1.8 and H1.6 (Garfinkel2015HP1BP3).

The protein's tripartite structure, with globular domains flanked by an unstructured NTD and a basic CTD, is reminiscent of the linker histone structure (Garfinkel2015HP1BP3). The binding of HP1BP3 to nucleosomal DNA involves cooperation between the globular domain and the CTD, with deletion of either domain significantly reducing chromatin affinity (Garfinkel2015HP1BP3). The DE region interacts with core histones and modulates DNA binding, with its deletion increasing chromatin residence time (Garfinkel2015HP1BP3). HP1BP3 also contains a canonical HP1 binding motif, PQVKL, crucial for its localization in heterochromatin (Garfinkel2015HP1BP3). Two splice variants, HP1BP3a and HP1BP3b, are expressed in a tissue-specific manner (Garfinkel2015HP1BP3).

## Function
HP1BP3 is a chromatin-binding protein that plays a crucial role in maintaining chromatin structure and regulating gene expression in healthy human cells. It is related to the histone H1 family and is involved in chromatin dynamics, particularly in the transition between euchromatin and heterochromatin, which can activate or silence specific genes (Garfinkel2015HP1BP3; Dutta2014Profiling). HP1BP3 is predominantly localized in the nucleus, where it is enriched in heterochromatin regions, interacting with heterochromatin protein 1 (HP1) through a canonical binding motif (Garfinkel2015HP1BP3).

The protein's binding to chromatin is cell cycle-dependent, with a larger immobile fraction in the G1 phase compared to the S phase, and its binding affinity is modulated by phosphorylation (Garfinkel2015HP1BP3). HP1BP3 is essential for cell cycle regulation, particularly in the G1 to S phase transition, where it helps maintain heterochromatin integrity and influences the duration of the G1 phase, thereby affecting cell proliferation (Dutta2014Profiling).

In addition to its role in chromatin organization, HP1BP3 is involved in transcriptional regulation, affecting the expression of a subset of genes without altering global chromatin organization (Garfinkel2015HP1BP3). Its depletion leads to changes in gene expression and increased cell proliferation, highlighting its role in maintaining normal cellular function (Dutta2014Profiling).

## Clinical Significance
Alterations in the expression or function of the HP1BP3 gene have been implicated in several clinical conditions. In the context of cognitive aging and Alzheimer's disease, reduced levels of HP1BP3 are associated with cognitive decline. Knockdown of HP1BP3 in mice leads to cognitive deficits and transcriptional changes similar to those observed in aging human brains, including increased inflammation and neurodegeneration, which are common in Alzheimer's disease (Neuner2018Knockdown; Neuner2016Systems). This suggests that HP1BP3 could be a potential target for therapeutic interventions aimed at mitigating cognitive decline in aging and Alzheimer's disease.

In terms of growth and bone development, HP1BP3 deficiency in mice results in proportionate dwarfism and low bone mass, linked to alterations in the endocrine IGF-1 pathway. This deficiency leads to a significant reduction in circulating IGF-1 levels and changes in the expression of its binding proteins, which are crucial for normal growth and bone mineralization (Garfinkel2015Proportionate).

HP1BP3 also plays a role in cancer progression, particularly under hypoxic conditions. It is involved in regulating cell cycle and hypoxia-induced cancer progression, with its depletion increasing radio-chemo-sensitivity in cancer cells and affecting cancer stem cell self-renewal (Bamaprasad2024Profiling). These findings highlight the potential of HP1BP3 as a drug target in cancer treatment.

## Interactions
HP1BP3 interacts with heterochromatin protein 1 (HP1), a key player in heterochromatin formation. This interaction is facilitated by a canonical HP1 binding motif, PQVKL, located between the first two globular domains of HP1BP3. A mutation in this motif disrupts the interaction, leading to a loss of HP1BP3 enrichment in heterochromatin (Garfinkel2015HP1BP3). HP1BP3 is enriched in heterochromatin in an HP1-dependent manner, as evidenced by its co-localization with heterochromatin markers HP1α and H3K9me3 (Garfinkel2015HP1BP3).

HP1BP3 also interacts with nucleosomal DNA, exhibiting binding dynamics similar to those of histone H1. Its chromatin binding is influenced by its tripartite structure, which includes a central globular core and flanking C-terminal and N-terminal regions. Both the globular domain and the C-terminal domain are crucial for its high-affinity binding to nucleosomal DNA (Garfinkel2015HP1BP3). The protein's interaction with chromatin is dynamic and can be modulated by post-translational modifications such as phosphorylation (Garfinkel2015HP1BP3).

In Crassostrea hongkongensis, HP1BP3 interacts with the ChHsp70 promoter, acting as a negative regulator of Hsp70 transcription. This interaction is concentration-dependent and involves both protein-DNA and protein-protein interactions (Xu2017The).


## References


[1. (Neuner2018Knockdown) Sarah M. Neuner, Shengyuan Ding, and Catherine C. Kaczorowski. Knockdown of heterochromatin protein 1 binding protein 3 recapitulates phenotypic, cellular, and molecular features of aging. Aging Cell, December 2018. URL: http://dx.doi.org/10.1111/acel.12886, doi:10.1111/acel.12886. This article has 11 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1111/acel.12886)

[2. (Garfinkel2015Proportionate) Benjamin P. Garfinkel, Shiri Arad, Phuong T. Le, Michael Bustin, Clifford J. Rosen, Yankel Gabet, and Joseph Orly. Proportionate dwarfism in mice lacking heterochromatin protein 1 binding protein 3 (hp1bp3) is associated with alterations in the endocrine igf-1 pathway. Endocrinology, 156(12):4558–4570, September 2015. URL: http://dx.doi.org/10.1210/en.2015-1668, doi:10.1210/en.2015-1668. This article has 13 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1210/en.2015-1668)

[3. (Garfinkel2015HP1BP3) Benjamin P. Garfinkel, Naomi Melamed-Book, Eli Anuka, Michael Bustin, and Joseph Orly. Hp1bp3 is a novel histone h1 related protein with essential roles in viability and growth. Nucleic Acids Research, 43(4):2074–2090, February 2015. URL: http://dx.doi.org/10.1093/nar/gkv089, doi:10.1093/nar/gkv089. This article has 22 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1093/nar/gkv089)

[4. (Dutta2014Profiling) Bamaprasad Dutta, Yan Ren, Piliang Hao, Kae Hwan Sim, Esther Cheow, Sunil Adav, James P. Tam, and Siu Kwan Sze. Profiling of the chromatin-associated proteome identifies hp1bp3 as a novel regulator of cell cycle progression. Molecular & Cellular Proteomics, 13(9):2183–2197, September 2014. URL: http://dx.doi.org/10.1074/mcp.M113.034975, doi:10.1074/mcp.m113.034975. This article has 53 citations.](https://doi.org/10.1074/mcp.M113.034975)

[5. (Xu2017The) Delin Xu, Qin Yang, Miao Cui, and Qizhong Zhang. The novel transcriptional factor hp1bp3 negatively regulates hsp70 transcription in crassostrea hongkongensis. Scientific Reports, May 2017. URL: http://dx.doi.org/10.1038/s41598-017-01573-y, doi:10.1038/s41598-017-01573-y. This article has 5 citations and is from a peer-reviewed journal.](https://doi.org/10.1038/s41598-017-01573-y)

6. (Bamaprasad2024Profiling) Profiling dynamic chromatome reveals HP1BP3 as a key regulator of cell cycle and hypoxia cancer progression. This article has 0 citations.

[7. (Neuner2016Systems) Sarah M. Neuner, Benjamin P. Garfinkel, Lynda A. Wilmott, Bogna M. Ignatowska-Jankowska, Ami Citri, Joseph Orly, Lu Lu, Rupert W. Overall, Megan K. Mulligan, Gerd Kempermann, Robert W. Williams, Kristen M.S. O’Connell, and Catherine C. Kaczorowski. Systems genetics identifies hp1bp3 as a novel modulator of cognitive aging. Neurobiology of Aging, 46:58–67, October 2016. URL: http://dx.doi.org/10.1016/j.neurobiolaging.2016.06.008, doi:10.1016/j.neurobiolaging.2016.06.008. This article has 34 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1016/j.neurobiolaging.2016.06.008)