Trithorax-group proteins

Last updated

Trithorax-group proteins (TrxG) are a heterogeneous collection of proteins whose main action is to maintain gene expression. They can be categorized into three general classes based on molecular function:

Contents

  1. histone-modifying TrxG proteins
  2. chromatin-remodeling TrxG proteins
  3. DNA-binding TrxG proteins,

plus other TrxG proteins not categorized in the first three classes. [1]

Discovery

The founding member of TrxG proteins, trithorax (trx), was discovered ~1978 by Philip Ingham as part of his doctoral thesis while a graduate student in the laboratory of J.R.S. Whittle at the University of Sussex. [2] Histone-lysine N-methyltransferase 2A is the human homolog of trx. [2]

Members of Trithorax Group Proteins:
NameSymbol(s)
absent, small or homeotic discs 1ash1
absent, small or homeotic discs 2ash2
brahmabrm
Brahma associated protein 55kDBap55
Brahma associated protein 60 kDBap60
dalaodalao
dominodom
Enhancer of bithoraxE(bx)
enhancer of yellow 3SAYP or e(y)3
eyelideld or osa
female sterile (1) homeoticfs(1)h
grappagpp
Imitation SWIIswi
kismetkis
little imaginal discslid
lola likelolal
modifier of mdg 4mod(mdg4), E(var)3-93D, or doom
moiramor
Nucleosome remodeling factor-38kDNurf38
trithoraxtrx
Trithorax likeTrl
Ubiquitously transcribed tetratricopeptide repeat, X chromosomeUtx
verthandivtd
zestez

The table contains names of Drosophila TrxG members. Homologs in other species may have different names.

Function

Trithorax-group proteins typically function in large complexes formed with other proteins. The complexes formed by TrxG proteins are divided into two groups: histone-modifying complexes and ATP-dependent chromatin-remodeling complexes. The main function of TrxG proteins, along with polycomb group (PcG) proteins, is regulating gene expression. Whereas PcG proteins are typically associated with gene silencing, TrxG proteins are most commonly linked to gene activation. The trithorax complex activates gene transcription by inducing trimethylation of lysine 4 of histone H3 (H3K4me3) at specific sites in chromatin recognized by the complex. [1] Ash1 domain is involved in H3K36 methylation. Trithorax complex also interacts with CBP (CREB binding protein) which is an acetyltransferase to acetylate H3K27. [3] This gene activation is reinforced by acetylation of histone H4. The actions of TrxG proteins are often described as 'antagonistic' of PcG proteins function. [4] Aside from gene regulation, evidence suggests TrxG proteins are also involved in other processes including apoptosis, cancer, and stress responses. [5] [6] [7]

Role in development

During development, TrxG proteins maintain activation of required genes, particularly the Hox genes, after maternal factors are depleted. [8] This is accomplished by preserving the epigenetic marks, specifically H3K4me3, established by maternally-supplied factors. [9] TrxG proteins are also implicated in X-chromosome inactivation, which occurs during early embryogenesis. [10] As of 2011 it is unclear whether TrxG activity is required in every cell during the entire development of an organism or only during certain stages in certain cell types. [11]

See also

Related Research Articles

<span class="mw-page-title-main">Histone</span> Family proteins package and order the DNA into structural units called nucleosomes.

In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei and in most Archaeal phyla. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn are wrapped into 30-nanometer fibers that form tightly packed chromatin. Histones prevent DNA from becoming tangled and protect it from DNA damage. In addition, histones play important roles in gene regulation and DNA replication. Without histones, unwound DNA in chromosomes would be very long. For example, each human cell has about 1.8 meters of DNA if completely stretched out; however, when wound about histones, this length is reduced to about 90 micrometers (0.09 mm) of 30 nm diameter chromatin fibers.

Heterochromatin is a tightly packed form of DNA or condensed DNA, which comes in multiple varieties. These varieties lie on a continuum between the two extremes of constitutive heterochromatin and facultative heterochromatin. Both play a role in the expression of genes. Because it is tightly packed, it was thought to be inaccessible to polymerases and therefore not transcribed; however, according to Volpe et al. (2002), and many other papers since, much of this DNA is in fact transcribed, but it is continuously turned over via RNA-induced transcriptional silencing (RITS). Recent studies with electron microscopy and OsO4 staining reveal that the dense packing is not due to the chromatin.

<span class="mw-page-title-main">Cellular differentiation</span> Developmental biology

Cellular differentiation is the process in which a stem cell changes from one type to a differentiated one. Usually, the cell changes to a more specialized type. Differentiation happens multiple times during the development of a multicellular organism as it changes from a simple zygote to a complex system of tissues and cell types. Differentiation continues in adulthood as adult stem cells divide and create fully differentiated daughter cells during tissue repair and during normal cell turnover. Some differentiation occurs in response to antigen exposure. Differentiation dramatically changes a cell's size, shape, membrane potential, metabolic activity, and responsiveness to signals. These changes are largely due to highly controlled modifications in gene expression and are the study of epigenetics. With a few exceptions, cellular differentiation almost never involves a change in the DNA sequence itself. However, metabolic composition does get altered quite dramatically where stem cells are characterized by abundant metabolites with highly unsaturated structures whose levels decrease upon differentiation. Thus, different cells can have very different physical characteristics despite having the same genome.

Histone methylation is a process by which methyl groups are transferred to amino acids of histone proteins that make up nucleosomes, which the DNA double helix wraps around to form chromosomes. Methylation of histones can either increase or decrease transcription of genes, depending on which amino acids in the histones are methylated, and how many methyl groups are attached. Methylation events that weaken chemical attractions between histone tails and DNA increase transcription because they enable the DNA to uncoil from nucleosomes so that transcription factor proteins and RNA polymerase can access the DNA. This process is critical for the regulation of gene expression that allows different cells to express different genes.

Polycomb-group proteins are a family of protein complexes first discovered in fruit flies that can remodel chromatin such that epigenetic silencing of genes takes place. Polycomb-group proteins are well known for silencing Hox genes through modulation of chromatin structure during embryonic development in fruit flies. They derive their name from the fact that the first sign of a decrease in PcG function is often a homeotic transformation of posterior legs towards anterior legs, which have a characteristic comb-like set of bristles.

Chromatin remodeling is the dynamic modification of chromatin architecture to allow access of condensed genomic DNA to the regulatory transcription machinery proteins, and thereby control gene expression. Such remodeling is principally carried out by 1) covalent histone modifications by specific enzymes, e.g., histone acetyltransferases (HATs), deacetylases, methyltransferases, and kinases, and 2) ATP-dependent chromatin remodeling complexes which either move, eject or restructure nucleosomes. Besides actively regulating gene expression, dynamic remodeling of chromatin imparts an epigenetic regulatory role in several key biological processes, egg cells DNA replication and repair; apoptosis; chromosome segregation as well as development and pluripotency. Aberrations in chromatin remodeling proteins are found to be associated with human diseases, including cancer. Targeting chromatin remodeling pathways is currently evolving as a major therapeutic strategy in the treatment of several cancers.

<span class="mw-page-title-main">EZH2</span> Protein-coding gene in the species Homo sapiens

Enhancer of zeste homolog 2 (EZH2) is a histone-lysine N-methyltransferase enzyme encoded by EZH2 gene, that participates in histone methylation and, ultimately, transcriptional repression. EZH2 catalyzes the addition of methyl groups to histone H3 at lysine 27, by using the cofactor S-adenosyl-L-methionine. Methylation activity of EZH2 facilitates heterochromatin formation thereby silences gene function. Remodeling of chromosomal heterochromatin by EZH2 is also required during cell mitosis.

<span class="mw-page-title-main">PRC2</span>

PRC2 is one of the two classes of polycomb-group proteins or (PcG). The other component of this group of proteins is PRC1.

Cellular memory modules are a form of epigenetic inheritance that allow cells to maintain their original identity after a series of cell divisions and developmental processes. Cellular memory modules implement these preserved characteristics into transferred environments through transcriptional memory. Cellular memory modules are primarily found in Drosophila.

Plants depend on epigenetic processes for proper function. Epigenetics is defined as "the study of changes in gene function that are mitotically and/or meiotically heritable and that do not entail a change in DNA sequence". The area of study examines protein interactions with DNA and its associated components, including histones and various other modifications such as methylation, which alter the rate or target of transcription. Epi-alleles and epi-mutants, much like their genetic counterparts, describe changes in phenotypes due to epigenetic mechanisms. Epigenetics in plants has attracted scientific enthusiasm because of its importance in agriculture.

Epigenetics of human development is the study of how epigenetics effects human development.

H3K4me3 is an epigenetic modification to the DNA packaging protein Histone H3 that indicates tri-methylation at the 4th lysine residue of the histone H3 protein and is often involved in the regulation of gene expression. The name denotes the addition of three methyl groups (trimethylation) to the lysine 4 on the histone H3 protein.

H3K27me3 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the tri-methylation of lysine 27 on histone H3 protein.

<span class="mw-page-title-main">Thomas Jenuwein</span> German scientist

Thomas Jenuwein is a German scientist working in the fields of epigenetics, chromatin biology, gene regulation and genome function.

H3K9me3 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the tri-methylation at the 9th lysine residue of the histone H3 protein and is often associated with heterochromatin.

H3K4me1 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the mono-methylation at the 4th lysine residue of the histone H3 protein and often associated with gene enhancers.

H3K14ac is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the acetylation at the 14th lysine residue of the histone H3 protein.

H3K36me2 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the di-methylation at the 36th lysine residue of the histone H3 protein.

Vincenzo Pirrotta is a biologist known for his work on Drosophila and polycomb group proteins. Born in Palermo, Italy, Pirotta migrated to the United States and enrolled at Harvard University. While at Harvard, he obtained undergraduate, graduate, and postdoctoral fellowships in physical chemistry and molecular biology. He later moved to Europe where he began studying gene regulation in bacteriophages and Drosophila. He was appointed assistant professor at the University of Basel in 1972. Pirotta returned to the United States, earning a full professorship at the Baylor College of Medicine in 1992. He then took up the position of professor of zoology at the University of Geneva in 2002, and in 2004 became a distinguished professor of molecular biology and biochemistry at Rutgers University.

H3R26me2 is an epigenetic modification to the DNA packaging protein histone H3. It is a mark that indicates the di-methylation at the 26th arginine residue of the histone H3 protein. In epigenetics, arginine methylation of histones H3 and H4 is associated with a more accessible chromatin structure and thus higher levels of transcription. The existence of arginine demethylases that could reverse arginine methylation is controversial.

References

  1. 1 2 Schuettengruber B, Chourrout D, Vervoort M, Leblanc B, Cavalli G (February 2007). "Genome regulation by polycomb and trithorax proteins". Cell. 128 (4): 735–45. doi: 10.1016/j.cell.2007.02.009 . PMID   17320510.
  2. 1 2 Ingham PW (1998). "trithorax and the regulation of homeotic gene expression in Drosophila: a historical perspective". Int. J. Dev. Biol. 42 (3): 423–9. PMID   9654027.
  3. Geisler, Sarah J.; Paro, Renato (2015-09-01). "Trithorax and Polycomb group-dependent regulation: a tale of opposing activities". Development. 142 (17): 2876–2887. doi: 10.1242/dev.120030 . hdl: 20.500.11850/104579 . ISSN   0950-1991. PMID   26329598.
  4. Grimaud C, Nègre N, Cavalli G (2006). "From genetics to epigenetics: the tale of Polycomb group and trithorax group genes". Chromosome Res. 14 (4): 363–75. doi:10.1007/s10577-006-1069-y. PMID   16821133. S2CID   19504262.
  5. Tyagi S, Herr W (October 2009). "E2F1 mediates DNA damage and apoptosis through HCF-1 and the MLL family of histone methyltransferases". EMBO J. 28 (20): 3185–95. doi:10.1038/emboj.2009.258. PMC   2771094 . PMID   19763085.
  6. Siebold AP, Banerjee R, Tie F, Kiss DL, Moskowitz J, Harte PJ (January 2010). "Polycomb Repressive Complex 2 and Trithorax modulate Drosophila longevity and stress resistance". Proc. Natl. Acad. Sci. U.S.A. 107 (1): 169–74. Bibcode:2010PNAS..107..169S. doi: 10.1073/pnas.0907739107 . PMC   2806727 . PMID   20018689.
  7. Bagchi A, Papazoglu C, Wu Y, Capurso D, Brodt M, Francis D, Bredel M, Vogel H, Mills AA (February 2007). "CHD5 is a tumor suppressor at human 1p36". Cell. 128 (3): 459–75. doi: 10.1016/j.cell.2006.11.052 . PMID   17289567.
  8. Brock HW, Fisher CL (March 2005). "Maintenance of gene expression patterns". Dev. Dyn. 232 (3): 633–55. doi: 10.1002/dvdy.20298 . PMID   15704101.
  9. Soshnikova N (August 2011). "Dynamics of Polycomb and Trithorax activities during development". Birth Defects Research Part A: Clinical and Molecular Teratology. 91 (8): 781–7. doi:10.1002/bdra.20774. PMID   21290568.
  10. Pullirsch D, Härtel R, Kishimoto H, Leeb M, Steiner G, Wutz A (March 2010). "The Trithorax group protein Ash2l and Saf-A are recruited to the inactive X chromosome at the onset of stable X inactivation". Development. 137 (6): 935–43. doi:10.1242/dev.035956. PMC   2834461 . PMID   20150277.
  11. Schuettengruber B, Martinez AM, Iovino N, Cavalli G (December 2011). "Trithorax group proteins: switching genes on and keeping them active". Nat. Rev. Mol. Cell Biol. 12 (12): 799–814. doi:10.1038/nrm3230. hdl: 21.11116/0000-0006-0774-0 . PMID   22108599. S2CID   19992445.