The DNA flexibility model suggests that H2A.Z is more likely than H2A to be found near transcriptional start sites.
Here we show that models based on both genetic or epigenetic information are able to predict the H2A.Z or H2A status of nucleosomes with an accuracy significantly greater than random, and that a flexibility-driven model of those sequences can predict the distribution of H2A.Z-containing nucleosomes observed near transcriptional start sites in vivo.
The first evidence of a transcriptional involvement for H2A.Z came from experiments in Tetrahymena thermophila, where H2A.Z was found to reside exclusively in the transcriptionally active macronucleus .
In Caenorhabditis elegans, the PHA-4 transcription factor (which belongs to the FoxA family) binds a known DNA sequence and recruits H2A.Z to the promoters of genes involved in pharyngeal development .
Within chromatin, the histone variant H2A.Z plays a role in many diverse nuclear processes including transcription, preventing the spread of heterochromatin and epigenetic transcriptional memory.
This association is interesting because like H2A.Z, H3 PhosS10 has been shown to be involved in processes requiring open and condensed chromatin, namely in transcription and chromosome condensation during mitosis .
Several systems have shown that H2A.Z functions in part to poise promoter chromatin for transcriptional activation, since it is remodelled from promoters of actively transcribing genes .
Furthermore, binding sites for c-myc are present within the upstream region of the H2A.Z-1 promoter (-459, -563) where they have been shown to specifically bind MYC and increase H2A.Z-1 transcription in response to estrogen .
In mammalian cells, H2A.Z was shown to be important for transactivation by transcription factors such as p53 and nuclear receptors ,, leading to local chromatin reorganization and transcriptional regulation.
Work in yeast suggest that H2A.Z regulates transcription either by creating unstable nucleosomes , by positioning nucleosomes , by making contacts with the transcription machinery and/or by maintaining active genes to the nuclear periphery .
Perhaps the most striking finding in this study is the fact that transcription results in the removal H2A.Z from transcribed regions.
A preference of those machines for canonical H2A would make the transcription-dependent H2A.Z depletion possible.
This battle between random H2A.Z incorporation and transcription-dependent H2A.Z depletion helps shaping the euchromatin and heterochromatin landscapes.
Despite all the work reviewed above, the mechanisms by which H2A.Z regulates transcription, silencing, genome stability, and developement remains largely unknown.
Our observations that H2A.Z is also important in regulating nucleosome positioning, in particular at the GAL1 promoter, may account for a mechanism by which H2A.Z regulates transcription.
Subsequently, experiments carried out in yeast have shown that H2A.Z could regulate transcription [,] and that its function is partially redundant with nucleosome remodeling complexes such as SAGA and Swi/Snf [].
On the other hand, work from our laboratory has shown that H2A.Z can interact with regulatory proteins and components of the transcriptional machinery [], arguing that H2A.Z may regulate gene expression through interactions with such downstream effectors.
H2A.Z has been shown to be quickly remodeled soon after gene induction [,–], a result that implies that the role of H2A.Z in positive gene transcription occurs at an early step.
Upon DNA damage, H2A.Z is first evicted from the p21 promoter, followed by the recruitment of the Tip60 histone acetyltransferase to activate p21 transcription. p400, a human Swr1 homolog, is required for the localization of H2A.Z, and largely colocalizes with H2A.Z at multiple promoters investigated.
Here we show that H2A.Z suppresses the p53 → p21 transcription and senescence responses.
Collectively, this study strongly suggests that certain sequence-specific transcription factors regulate transcription, in part, by preferentially positioning histone variant H2A.Z within chromatin.
Recent studies reveal that histones are removed and replaced to enable or restrict, respectively, access of the transcription machinery to regulate transcription.
Histone loss also occurs within transcription units to enable passage of the RNA polymerase, but in this case the histones are rapidly replaced, sometimes by 'variant' histones with specific properties that might serve as a memory of transcriptional competence.
Overall, the majority of genes identified encode histones, regulators of histone gene expression, histone chaperones, and other factors implicated in transcriptional control.
Furthermore, our results show that although RNA can interact with core histones, the synthesized RNA is not bound to the histones dissociated by transcription.
Our results indicate that core histones released during transcription can be bound to naked DNA and chromatin (with or without histones H1-H5).
Under ionic strength approaching physiological conditions we have observed that transcription causes nucleosome dissociation and histone redistribution within the template.
From the dynamic properties of excess histones bound to chromatin, we suggest a nucleosome transcription mechanism in which displaced histones are transiently bound to chromatin and finally are reassembled with DNA after the passage of the polymerase.
To further investigate the mechanism of inhibition of Tat-mediated transcription by HEXIM1, we tested the relative levels of transfected Tat protein in the presence of F:HEXIM1.
We sought to determine the consequences of ectopically expressed F:HEXIM1 on P-TEFb induced transcription in the absence of Tat.
HEXIM1 expression specifically represses transcription mediated by the direct activation of P-TEFb through artificial recruitment of GAL4-CycT1.
Our results differ somewhat from those obtained in the Zhou lab who found that exogenous expression of HEXIM1 affects both basal as well as Tat-induced transcription .
Moreover, we found that basal transcription from the LTR sequences was largely unaffected by over-expression of HEXIM1.
Histone modifications and histone modifying complexes have been traditionally associated with transcriptional regulation; however, recent studies indicated that the mechanisms involving the histone code play important roles in DNA replication, DNA damage detection and DNA repair.
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