Why are histones acetylated

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Schroeder, F. Antidepressant-like effects of the histone deacetylase inhibitor, sodium butyrate, in the mouse. Psychiatry 62 , 55—64 Several HDACs are differentially expressed in endometrial carcinomas [ 85 , ].

Inhibition of HDAC2 by valproate induces endometrial cell differentiation [ 80 ]. HDAC1 and 2 expression levels are upregulated in endometriosis in vitro [ 8 ]. Histone acetylation and aberrant levels of HDACs are also associated with endometriosis. HDAC 1 expression is seen to be significantly elevated during endometriosis compared to normal endometrium, and the level also correlates with low acetylation levels of H3 and H4 [ 9 , ]. It was seen again in a later study that HDAC 1 and 2 expression levels were high in endometriotic stromal cells compared to healthy endometrial stromal cells.

Differential expression of HDAC 1 and 2 was observed based on lesion type and localization in endometrioid cells [ 8 ]. A comparative study between ectopic and eutopic endometrial samples taken from women who have endometriosis showed that HDAC 1 gene expression was high in ectopic tissues while HDAC 2 expression levels were high in eutopic tissue samples. It should be noted that this study used total tissue samples with minimal sample size, and the total sample contained varied cell populations from various endometrial cycle stages.

The anti-inflammatory effects of SIRT1 have also been investigated in endometriosis. This study compared the action of SIRT1 and its activator resveratrol in endometriotic stromal cells and healthy endometrial stromal cells. They found that the activation of SIRT1 suppresses inflammatory responses in endometriotic stromal cells, while inhibition of SIRT1 can trigger inflammatory responses. Suggesting its crucial role in maintaining healthy endometrial stromal cells [ ] Fig.

HDACs also play a crucial role in implantation and decidualization. Loss of HDAC 3 is linked to decidualization defects and implantation failure in mice [ 7 ]. HDAC inhibitor TSA in endometrial stromal cells negatively regulates trophoblast invasion and facilitates decidualization, influencing embryo implantation [ 91 , 95 ] Fig. Since most of the studies on endometriosis and other endometrial pathologies compare healthy and diseased tissue samples, it is hard to tell if the epigenetic aberrations are the cause or effect of various endometrial pathologies.

Histone acetylation is a fundamental regulator of chromatin structure and gene expression. Many studies on endometrial tissues and cell lines have shown the involvement of aberrant levels of histone acetylation and HDACs in endometrial pathologies, especially endometrial carcinomas and endometriosis. The majority of HDACs studied seem to be elevated in endometrial carcinomas compared to the normal endometrium [ 8 , 85 ].

High levels of HDACs are also associated with endometriosis in many women. Furthermore, evidence suggests that histone acetylation and HDACs are involved in various endometrial pathologies [ 7 , 8 , 9 , 79 , 83 ]. However, most of these studies have not given any regard to the cyclic nature of the endometrium. HDACs are being studied as potential therapeutic targets for endometrial carcinomas and endometriosis; their effect reversed with HDAC inhibitors [ 79 , 83 ].

Global histone acetylation levels of H2AK5, H3K9, and H4K8 are found to be elevated in the early proliferative phase of the endometrium, then decline until ovulation. This study suggests that histone acetylation trends seem to follow a cyclic pattern in coordination with menstrual cycle events that require transcriptional activation and silencing [ 6 ].

HDACs function in conjunction with other epigenetic modulators, regulating molecular modifications in the endometrium [ ]. Studying the general levels of HDACs and histone acetylation in normal cyclic endometrium will give us insight into individual functions and targets of individual HDACs.

Because histone acetylation is a reversible epigenetic mark, studying its regulation will eventually help us to develop targeted therapies to improve the menstrual health of women. Cytopathology of the glandular lesions of the female genital tract. In: Orell SR, editor. Monographs in clinical cytology. Basel Suiza : Karger Eds; ISBN Google Scholar. Chapter 9 - structure, function, and evaluation of the female reproductive tract. Yen and Jaffe's reproductive endocrinology 8th edition.

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In: Menstrual cycle: IntechOpen. Accessed 17 Sept Wilson EW. In: Rennie PIC, editor. At present, there is virtually no information on the localization of modified chromatin in vivo.

Do these enzymatic activities modify a single nucleosome, or is chromatin structure perturbed over a larger distance? Where is the location of the modified chromatin structure with respect to binding sites for DNA-binding activators and repressors or for components of the basic transcription machinery such as TFIID or the Pol II holoenzyme?

In addition, the histone acetylases and deacetylases differ with respect to the individual lysine residues and specific histones that are affected, and there is limited information on how such differences affect chromatin structure and protein accessibility in vivo. These questions should be addressed in the near future, and it is likely that the answers will differ depending on the histone-modifying activity and the promoter.

However, accessibility to the promoter is also influenced strongly by 1 the inherent ability of a given DNA-binding protein to bind nucleosomal templates, 2 the inherent positioning of nucleosomes on particular promoter DNA sequences, 3 the intracellular levels of the DNA-binding proteins, 4 the inherent quality of the binding site, and 5 competition between binding sites in promoter regions and those located throughout the genome.

Furthermore, local perturbations of chromatin structure could affect the communication between enhancer-bound proteins and the general Pol II transcription machinery. Clearly, there is a complicated and poorly understood interplay between these additional parameters and the local state of histone acetylation.

Thus, to understand the molecular mechanism by which histone acetylation affects transcription of particular genes, it will be essential to experimentally determine the occupancy of the relevant promoter DNA sequences by activators, repressors, TFIID, and Pol II holoenzyme in vivo.

Although the effects of histone acetylation and deacetylation are typically viewed in terms of promoter accessibility, it is also possible that acetylated or deacetylated histones could serve as signals for interaction with proteins.

For example, the transcriptional repression domain of the Tup1 corepressor interacts with underacetylated forms of histones H3 and H4 Edmondson et al. In cases where histone acetylation or deacetylation is targeted, recognition of such signals by relatively general chromatin-associated proteins could lead to local chromatin structures that differ considerably from that of bulk chromatin.

For example, lysine 12 of histone H4 is preferentially acetylated in transcriptionally silent heterochromatin Braunstein et al. These observations are surprising because, in striking contrast to the usual correlation, histone acetylation is associated with deceased transcriptional activity. One explanation for this paradoxical situation is that the acetylated lysine 12 of histone H4 is recognized by proteins that lead to the formation of heterochromatin.

The molecular description of histone acetylases and deacetylases has revealed two fundamental principles. First, histone acetylases can be basic components of, or closely associated with, the Pol II machinery. Thus, recruitment of the Pol II machinery to promoters is concomitant with recruitment of histone acetylases, thereby providing a simple mechanism to account for the general correlation between histone acetylation and transcriptional activity. Second, some histone acetylases and deacetylases interact with specific DNA-binding activator and repressor proteins, strongly suggesting that they modulate transcriptional activity of specific promoters by locally perturbing chromatin structure.

Furthermore, specific targeting of chromatin modifying activities could occur independently of recruitment of the Pol II machinery, thereby providing an explanation for situations in the development of multicellular organisms, in which changes in chromatin structure precede changes in transcriptional activity. More speculatively, targeting of histone modifying activities to specific genomic regions could underlie long-range chromatin structures, such as occur in heterochromatin, locus control regions, and chromosome inactivation.

Given the recent excitement in this area and the powerful experimental tools now available, it should not be too long to wait for long-standing correlations to metamorphose into detailed molecular mechanisms.

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