Over the past 10 years, the study of histone acetyltransferases (HATs) has advanced significantly, and a number of HATs have been isolated from various organisms. It emerged that HATs are highly diverse and generally contain multiple subunits. The functions of the catalytic subunit depend largely on the context of the other subunits in the complex. We are just beginning to understand the specialized roles of HAT complexes in chromosome decondensation, DNA-damage repair and the modification of non-histone substrates, as well as their role in the broader epigenetic landscape, including the role of protein domains within HAT complexes and the dynamic interplay between HAT complexes and existing histone modifications.

Histone acetyltransferase complexes: one size doesn't fit all

Nuclear pore components are involved in the transcriptional regulation of dosage compensation in Drosophila

We describe a stable, multisubunit human histone acetyltransferase complex (hMSL) that contains homologs of the Drosophila dosage compensation proteins MOF, MSL1, MSL2, and MSL3. This complex shows strong specificity for histone H4 lysine 16 in chromatin in vitro, and RNA interference-mediated knockdown experiments reveal that it is responsible for the majority of H4 acetylation at lysine 16 in the cell. We also find that hMOF is a component of additional complexes, forming associations with host cell factor 1 and a protein distantly related to MSL1 (hMSL1v1). We find two versions of hMSL3 in the hMSL complex that differ by the presence of the chromodomain. Lastly, we find that reduction in the levels of hMSLs and acetylation of H4 at lysine 16 are correlated with reduced transcription of some genes and with a G2/M cell cycle arrest. This is of particular interest given the recent correlation of global loss of acetylation of lysine 16 in histone H4 with tumorigenesis.

A Human Protein Complex Homologous to the Drosophila MSL Complex Is Responsible for the Majority of Histone H4 Acetylation at Lysine 16

In many multicellular organisms, males have one X chromosome and females have two. Dosage compensation refers to a regulatory mechanism that insures the equalization of X-linked gene products in males and females. The mechanism has been studied at the molecular level in model organisms belonging to three distantly related taxa; in these organisms, equalization is achieved by shutting down one of the two X chromosomes in the somatic cells of females, by decreasing the level of transcription of the two doses of X-linked genes in females relative to males, or by increasing the level of transcription of the single dose of X-linked genes in males. The study of dosage compensation in these different forms has revealed the existence of an amazing number of interacting chromatin remodeling mechanisms that affect the function of entire chromosomes.

Chromatin remodeling in dosage compensation.

Dosage compensation is an epigenetic mechanism that normalizes gene expression from unequal copy numbers of sex chromosomes. Different organisms have evolved alternative molecular solutions to this task. In Drosophila melanogaster, transcription of the single male X chromosome is upregulated by twofold in a process orchestrated by the dosage compensation complex. Despite this conceptual simplicity, dosage compensation involves multiple coordinated steps to recognize and activate the entire X chromosome. We are only beginning to understand the intriguing interplay between multiple levels of local and long-range chromatin regulation required for the fine-tuned transcriptional activation of a heterogeneous gene population. This Review highlights the known facts and open questions of dosage compensation in D. melanogaster.

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Dosage compensation in Drosophila melanogaster : epigenetic fine-tuning of chromosome-wide transcription

The male-specific lethal (MSL) complex of Drosophila is responsible for the presence of a monoacetylated isoform of histone H4 (H4Ac16), found exclusively on the X chromosome of males. This particular covalent modification of histone H4 is correlated with a 2-fold enhancement of the transcription of most X-linked genes in Drosophila males, which is the basis of dosage compensation in this organism. Although widespread along the X chromosome, the MSL complex is not distributed uniformly, as can be seen by the indirect cytoimmunofluorescence staining of larval salivary-gland polytene chromosomes. This distribution pattern has been interpreted as a reflection of the tissue-specific transcriptional activity of the larval salivary gland and as an indication that the MSL complex associates with active chromatin. We have tested this hypothesis by comparing the chromosomal distribution of the complex in two different tissues. We performed this comparison by following the pattern of association of the complex at a specific site on salivary-gland chromosomes during larval development and determining whether an ectopic promoter located in a complex-devoid region of the X chromosome is able to attract the complex upon activation. Our results indicate that, in contrast to other chromatin-remodeling complexes that enhance transcription, the MSL complex targets active chromatin.

Georgette L. Sass

Papers

Male-specific lethal complex of Drosophila targets activated regions of the X chromosome for chromatin remodeling.