Histone deacetylase 7 is an
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
that in humans is encoded by the ''HDAC7''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
.
Function
Histones play a critical role in transcriptional regulation, cell cycle progression, and developmental events. Histone acetylation/deacetylation alters chromosome structure and affects transcription factor access to DNA. The protein encoded by this gene has sequence homology to members of the histone deacetylase family. This gene is orthologous to mouse HDAC7 gene whose protein promotes repression mediated via transcriptional corepressor SMRT. Multiple alternatively spliced transcript variants encoding several isoforms have been found for this gene.
HDAC7 has both structural and functional similarity to HDACs 4, 5, and 9, as these four HDACs make up the Class IIa of HDACs in higher eukaryotes. Class IIa HDACs are phosphorylated by calcium/calmodulin dependent-kindase (
CaMK
CAMK, also written as CaMK or CCaMK, is an abbreviation for the Ca2+/calmodulin-dependent protein kinase class of enzymes. CAMKs are activated by increases in the concentration of intracellular calcium ions (Ca2+) and calmodulin. When activated, t ...
) and protein kinase D (PKD) in response to kinase-dependent signaling. HDAC7 possesses little intrinsic deacetylase activity and therefore requires association with the class I HDAC,
HDAC3
Histone deacetylase 3 is an enzyme encoded by the ''HDAC3'' gene in both humans and mice.
Function
Histones are highly alkaline proteins that package and order DNA into structural units called nucleosomes, which comprise the major protein comp ...
in order to suppress gene expression. It has been demonstrated through crystal structures of the human HDAC7 that the catalytic domain of HDAC7 has an additional class IIa HDAC-specific zinc binding motif adjacent to the active site. This is most likely to allow for substrate recognition and protein-protein interactions that are necessary for class IIa HDAC enzymes.
Alternative functions
Although HDAC7 has shown to have little intrinsic deacetylase activity, studies have shown that HDAC7 may have various alternative functions related to development, proliferation, and inflammation.
One study showed that HDAC7 suppresses proliferation and
β-catenin
Catenin beta-1, also known as beta-catenin (β-catenin), is a protein that in humans is encoded by the ''CTNNB1'' gene.
Beta-catenin is a dual function protein, involved in regulation and coordination of cell–cell adhesion and gene transcriptio ...
activity in chondrocytes. This was shown by knocking out HDAC7 in mice, which then resulted in increased levels of the cell cycle regulator,
cyclin D3
G1/S-specific cyclin-D3 is a protein that in humans is encoded by the ''CCND3'' gene.
Function
The protein encoded by this gene belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in protein ...
; decreased levels of the tumor suppressor,
p21
p21Cip1 (alternatively p21Waf1), also known as cyclin-dependent kinase inhibitor 1 or CDK-interacting protein 1, is a cyclin-dependent kinase inhibitor (CKI) that is capable of inhibiting all cyclin/CDK complexes, though is primarily associated ...
; and increased levels of active beta-catenin. Since each of these contribute to regulating cell proliferation, deletion of HDAC7 increased
chondrocyte
Chondrocytes (, from Greek χόνδρος, ''chondros'' = cartilage + κύτος, ''kytos'' = cell) are the only cells found in healthy cartilage. They produce and maintain the cartilaginous matrix, which consists mainly of collagen and proteog ...
proliferation. This study also showed that signaling via the
insulin
Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...
/
Insulin-like growth factor 1
Insulin-like growth factor 1 (IGF-1), also called somatomedin C, is a hormone similar in molecular structure to insulin which plays an important role in childhood growth, and has anabolic effects in adults.
IGF-1 is a protein that in humans is ...
receptor led to increased levels of HDAC7 in the cytosol than the nucleus and increased levels of active β-catenin, indicating that HDAC7 associates with β-catenin. During
chondrogenesis
Chondrogenesis is the process by which cartilage is developed.
Cartilage in fetal development
In embryogenesis, the skeletal system is derived from the mesoderm germ layer. Chondrification (also known as chondrogenesis) is the process by which ...
, HDAC7 is translocated to the cytosol to be degraded, indicating that generally HDAC7 represses β-catenin activity in chondrocytes.
Another study supported the conclusion that HDAC7 and β-catenin associate together by demonstrating that HDAC7 controls endothelial cell growth through modulation of β-catenin. This was shown in the opposite way from the previous study, in that HDAC7 was overexpressed rather than removed. They found that overexpression of HDAC7 prevented nuclear translocation of β-catenin which then coincided with downregulation of the cell cycle regulator,
cyclin D1
Cyclin D1 is a protein that in humans is encoded by the ''CCND1'' gene.
Gene expression
The CCND1 gene encodes the cyclin D1 protein. The human CCND1 gene is located on the long arm of chromosome 11 (band 11q13). It is 13,388 base pairs lon ...
. Overall, this study demonstrated that HDAC7 once again interacts with β-catenin to keep endothelial cells in a low proliferation stage.
Not only does HDAC7 play a role in the proliferation of cell growth in chondrocytes and endothelial cells, but it has also been demonstrated that HDAC7 is a crucial player in cancer cell proliferation through a study that showed mechanistic insight into the contribution of HDAC7 to tumor progression. This study showed that knockdown of HDAC7 resulted in significant cell arrest between the G(1) and S phases of the cell cycle. Subsequently, HDAC7 knockdown suppressed c-
Myc
''Myc'' is a family of regulator genes and proto-oncogenes that code for transcription factors. The ''Myc'' family consists of three related human genes: ''c-myc'' (MYC), ''l-myc'' (MYCL), and ''n-myc'' (MYCN). ''c-myc'' (also sometimes referre ...
expression which in turn blocked cell cycle progression. Through
chromatin immunoprecipitation Chromatin immunoprecipitation (ChIP) is a type of immunoprecipitation experimental technique used to investigate the interaction between proteins and DNA in the cell. It aims to determine whether specific proteins are associated with specific genom ...
assays, it was shown that HDAC7 directly binds with the c-Myc gene and therefore HDAC7 silencing decreased c-Myc mRNA levels.
Outside of proliferation, an additional study demonstrated that HDAC7 promotes inflammatory responses in
macrophages
Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...
. This was shown by overexpression of HDAC7 in inflammatory macrophages in mice. This overexpression promoted
lipopolysaccharide
Lipopolysaccharides (LPS) are large molecules consisting of a lipid and a polysaccharide that are bacterial toxins. They are composed of an O-antigen, an outer core, and an inner core all joined by a covalent bond, and are found in the outer m ...
(LPS)-inducible expression of HDAC-dependent genes via a
HIF-1alpha
Hypoxia-inducible factor 1-alpha, also known as HIF-1-alpha, is a subunit of a heterodimeric transcription factor hypoxia-inducible factor 1 (HIF-1) that is encoded by the ''HIF1A'' gene. The Nobel Prize in Physiology or Medicine 2019 was awarded ...
-dependent mechanism. This demonstrated that HDAC7 may be a viable target for developing new anti-inflammatory drugs.
In this vein, TMP195 and JM63
are the most potent HDAC7 inhibitors. However, both compounds are not selective amongst class IIa HDACs, pointing to the need to develop HDAC7 selective inhibitors to further validate HDAC7 as an anti-inflammatory target.
Interactions
HDAC7A has been shown to
interact
Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with:
*
BCL6
Bcl-6 (B-cell lymphoma 6) is a protein that in humans is encoded by the ''BCL6'' gene. BCL6 is a master transcription factor for regulation of T follicular helper cells (TFH cells) proliferation. BCL6 has three evolutionary conserved structural do ...
,
*
Endothelin receptor type A
Endothelin receptor type A, also known as ETA, is a human G protein-coupled receptor.
Interactions
Endothelin receptor type A has been shown to interact with HDAC7A and HTATIP.
See also
* Endothelin receptor
There are at least four known ...
,
*
HDAC3
Histone deacetylase 3 is an enzyme encoded by the ''HDAC3'' gene in both humans and mice.
Function
Histones are highly alkaline proteins that package and order DNA into structural units called nucleosomes, which comprise the major protein comp ...
,
*
HTATIP
Histone acetyltransferase KAT5 is an enzyme that in humans is encoded by the ''KAT5'' gene. It is also commonly identified as TIP60.
The protein encoded by this gene belongs to the MYST family of histone acetyl transferases (HATs) and was origina ...
,
*
IKZF1
DNA-binding protein Ikaros also known as Ikaros family zinc finger protein 1 is a protein that in humans is encoded by the ''IKZF1'' gene.
Ikaros - transcription factor
Ikaros is a transcription factor that is encoded by the ''IKZF'' genes of ...
,
and
*
Nuclear receptor co-repressor 1
The nuclear receptor co-repressor 1 also known as thyroid-hormone- and retinoic-acid-receptor-associated co-repressor 1 (TRAC-1) is a protein that in humans is encoded by the ''NCOR1'' gene.
NCOR1 is a transcriptional coregulatory protein which c ...
.
[
]
See also
* Histone deacetylase
Histone deacetylases (, HDAC) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on a histone, allowing the histones to wrap the DNA more tightly. This is important because DNA is wrapped around his ...
References
Further reading
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External links
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