Histone methylation by the Drosophila epigenetic transcriptional regulator Ash1

Abstract

The establishment and maintenance of mitotic and meiotic stable (epigenetic) transcription patterns is fundamental for cell determination and function. Epigenetic regulation of transcription is mediated by epigenetic activators and repressors, and may require the establishment, 'spreading' and maintenance of epigenetic signals. Although these signals remain unclear, it has been proposed that chromatin structure and consequently post-translational modification of histones may have an important role in epigenetic gene expression. Here we show that the epigenetic activator Ash1 (ref. 5) is a multi-catalytic histone methyl-transferase (HMTase) that methylates lysine residues 4 and 9 in H3 and 20 in H4. Transcriptional activation by Ash1 coincides with methylation of these three lysine residues at the promoter of Ash1 target genes. The methylation pattern placed by Ash1 may serve as a binding surface for a chromatin remodelling complex containing the epigenetic activator Brahma (Brm), an ATPase, and inhibits the interaction of epigenetic repressors with chromatin. Chromatin immunoprecipitation indicates that epigenetic activation of Ultrabithorax transcription in Drosophila coincides with trivalent methylation by Ash1 and recruitment of Brm. Thus, histone methylation by Ash1 may provide a specific signal for the establishment of epigenetic, active transcription patterns.

Epigenetics and cancer

“…MLL1 has been found to associate with other epigenetic regulators, such as the HAT CBP (Ernst et al 2001) andINI1 (Rozenblatt-Rosen et al 1998), a subunit of the SWI/SNF nucleosome remodeling complex, and one study found MLL1 to reside in a large protein assembly containing subunits capable of regulating transcription preinitiation, nucleosome remodeling, histone acetylation, and histone methylation (Nakamura et al 2002). A similarly orchestrated epigenetic regulation was demonstrated for the Drosophila Trithorax-like protein Ash1, a histone methyltransferase (HMT) capable of methylating Lys 4 and Lys 9 of histone H3 and Lys 20 on histone H4 (Beisel et al 2002). The Ash1-specific methylation imprint was found to displace HP1 and PcG proteins, which are normally bound to repressed genes, and instead facilitates the binding of the Brahma chromatin remodeling complex (Beisel et al 2002).…”

Eukaryotic regulatory RNAs: an answer to the ‘genome complexity’ conundrum

“…Recent studies by Sanchez-Elsner (Sanchez-Elsner et al 2006) further showed that these intergenic transcripts from the TRE at the Ubx locus mediate transcriptional activation of Ubx by recruiting the epigenetic regulator Ash1 to the TRE elements. Ash1 is a histone methyltransferase (HMT) that promotes transcriptional activation by trimethylating H3K4, H3K9, and H4K20 (Beisel et al 2002) and is essential for the tissue-specific expression of Ubx (Beisel et al 2002 and references therein). Therefore, intergenic transcripts derived from the TRE locus mediate the recruitment of Ash1 to the TRE DNA elements of Ubx.…”

The role of components of the chromatin modification machinery in carcinogenesis of clear cell carcinoma of the ovary (Review)

“…Results using siRNA-knockdown approach indicate that ARID1A is required for cell-cycle arrest (26). Ubiquitination of H2B was associated with transcriptional activation (45). For example, ubiquitinated H2B has been identified in the yeast Saccharomyces cerevisiae, and mutation of the conserved ubiquitination site is shown to confer defects in mitotic cell growth and meiosis.…”