A common landmark of activated genes is the presence of trimethylation on lysine 4 of histone H3 (H3K4) at promoter regions. Set1/COMPASS was the founding member and is the only H3K4 methylase in Saccharomyces cerevisiae; however, in mammals, at least six H3K4 methylases, Set1A and Set1B and MLL1 to MLL4, are found in COMPASS-like complexes capable of methylating H3K4. To gain further insight into the different roles and functional targets for the H3K4 methylases, we have undertaken a genome-wide analysis of H3K4 methylation patterns in wild-type Mll1 ؉/؉ and Mll1 ؊/؊ mouse embryonic fibroblasts (MEFs). We found that Mll1 is required for the H3K4 trimethylation of less than 5% of promoters carrying this modification. Many of these genes, which include developmental regulators such as Hox genes, show decreased levels of RNA polymerase II recruitment and expression concomitant with the loss of H3K4 methylation. Although Mll1 is only required for the methylation of a subset of Hox genes, menin, a component of the Mll1 and Mll2 complexes, is required for the overwhelming majority of H3K4 methylation at Hox loci. However, the loss of MLL3/MLL4 and/or the Set1 complexes has little to no effect on the H3K4 methylation of Hox loci or their expression levels in these MEFs. Together these data provide insight into the redundancy and specialization of COMPASS-like complexes in mammals and provide evidence for a possible role for Mll1-mediated H3K4 methylation in the regulation of transcriptional initiation.The mixed-lineage leukemia gene (MLL1) is involved in numerous translocations found in several human acute leukemias (2,43,53). Chromosomal translocations in the MLL1 gene result in hematological malignancies, including acute myeloid and lymphoid leukemia. Although these cytogenetic abnormalities were discovered over 25 years ago, little is known about the biochemical functions of MLL1, its protein complexes, its translocation partners, and particularly, why these translocations result in leukemia. MLL1 is one of at least six genes encoding histone methyltransferases in mammals that methylate histone H3 on lysine 4 (H3K4), a posttranslational mark primarily associated with promoters of active genes (49). Much of our knowledge of the implementation of this mark comes from studies of Set1/COMPASS in the yeast Saccharomyces cerevisiae. The first H3K4 methylase complex to be identified, COMPASS, was purified from yeast and contains Set1 and seven other polypeptides, named Cps60 to Cps15 according to their size in yeast (30). COMPASS is capable of mono-, di-, and trimethylating H3K4 (20,42,48,56). Subsequently, it was determined that six mammalian Set1 homologs, MLL1 to MLL4 (KMT2A to KMT2D) and human Set1A and human Set1B (KMT2F and KMT2G), are found in COMPASS-like complexes, all capable of methylating H3K4 (5,15,16,23,38,49,59).We have recently shown that human Set1A/Set1B function most similarly to yeast COMPASS and mediate the bulk of the H3K4 trimethylation in mammalian cell extracts (57). In contrast, the members of th...
Segmentation is an important process that is frequently used during development to segregate groups of cells with distinct features. Segmental compartments provide a mechanism for generating and organizing regional properties along an embryonic axis and within tissues. In vertebrates the development of two major systems, the hindbrain and the paraxial mesoderm, displays overt signs of compartmentalization and depends on the process of segmentation for their functional organization. The hindbrain plays a key role in regulating head development, and it is a complex coordination center for motor activity, breathing rhythms, and many unconscious functions. The paraxial mesoderm generates somites, which give rise to the axial skeleton. The cellular processes of segmentation in these two systems depend on ordered patterns of Hox gene expression as a mechanism for generating a combinatorial code that specifies unique identities of the segments and their derivatives. In this review, we compare and contrast the signaling inputs and transcriptional mechanisms by which Hox gene regulatory networks are established during segmentation in these two different systems.
Hoxa2 gene is a primary player in regulation of craniofacial programs of head development in vertebrates. Here we investigate the evolution of a Hoxa2 neural crest enhancer identified originally in mouse by comparing and contrasting the fugu hoxa2a and hoxa2b genes with their orthologous teleost and mammalian sequences. Using sequence analyses in combination with transgenic regulatory assays in zebrafish and mouse embryos we demonstrate subfunctionalization of regulatory activity for expression in hindbrain segments and neural crest cells between these two fugu co-orthologs. hoxa2a regulatory sequences have retained the ability to mediate expression in neural crest cells while those of hoxa2b include cis-elements that direct expression in rhombomeres. Functional dissection of the neural crest regulatory potential of the fugu hoxa2a and hoxa2b genes identify the previously unknown cis-element NC5, which is implicated in generating the differential activity of the enhancers from these genes. The NC5 region plays a similar role in the ability of this enhancer to mediate reporter expression in mice, suggesting it is a conserved component involved in control of neural crest expression of Hoxa2 in vertebrate craniofacial development.
The novel gene ashwin was isolated in a differential display screen for genes activated or up-regulated early in neural specification. ashwin is expressed maternally and zygotically, and it is up-regulated in the neural ectoderm after the midgastrula stage. It is expressed in the neural plate and later in the embryonic brain, eyes, and spinal cord. Overexpression of ashwin in whole embryos leads to anterior truncations and other defects. However, a second Organizer does not form, and the secondary axial structures may result from splitting of the Organizer, rather than axis duplication. Morpholino oligonucleotide-mediated reduction in ashwin expression leads to lethality or abnormalities in gastrulation, as well as significant apoptosis in midgastrula embryos. Apoptosis is also observed in midgastrula embryos overexpressing ashwin. Coexpression of ashwin with the bone morphogenetic protein-4 antagonist noggin has a synergistic effect on neural-specific gene expression in isolated animal cap ectoderm. Ashwin has no previously characterized domains, although two nuclear localization signals can be identified. Orthologues have been identified in the human, mouse, chicken, and pufferfish genomes. Our results suggest that ashwin regulates cell survival and anteroposterior patterning.
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