MLL, a mammalian trithorax- group gene, functions as a transcriptional maintenance factor in morphogenesis

Abstract

Determinative events in vertebrate embryogenesis appear to require the continuous expression of spatial regulators such as the clustered homeobox genes. The mechanisms that govern long-term patterns of gene expression are not well understood. In Drosophila, active and silent states of developmentally regulated loci are maintained by trithorax and Polycomb group. We have examined the developmental role of a mammalian homolog of trx and putative oncogene, Mll. Knockout mice reveal that Mll is required for maintenance of gene expression early in embryogenesis. Downstream targets of Mll including Hoxa7 are activated appropriately in the absence of Mll but require Mll for sustaining their expression. The Mll؊͞؊ phenotype manifests later in development and is characterized by branchial arch dysplasia and aberrant segmental boundaries of spinal ganglia and somites. Thus, Mll represents an essential mechanism of transcriptional maintenance in mammalian development, which functions in multiple morphogenetic processes.

Epigenetic regulations in hematopoietic Hox code

“…Overexpression of Cdx4 can activate a reporter gene driven by Cdx-protein-binding sites within a Hoxa9 gene. However, in a hematopoietic cell line, Cdx4-Hoxa9 biding is abolished by ablation of menin (Yan et al, 2006a), which is a cofactor of the histone methyltransferase-MLL complex (Yu et al, 1998;Yokoyama et al, 2004Yokoyama et al, , 2005. These results suggest that an active chromatin domain is a prerequisite for formation of the Cdx-Hox transcription initiating complex.…”

MLL: How complex does it get?

“…Targeted homozygous disruption of Mll in mice is embryonic lethal and, similar to trx mutants in flies, Hox gene expression is initiated but not maintained in these animals [Yu et al, 1998]. Lethality at day E10.5 is associated with numerous defects in segmental identity.…”

ALL-1/MLL1, a homologue of Drosophila TRITHORAX, modifies chromatin and is directly involved in infant acute leukaemia

“…The TrxG and PcG proteins are not required for initiation of HOX genes activity, but act to maintain transcriptional states through later stages of development (reviewed in Brock and van Lohuizen, 2001;Simon and Tamkun, 2002). ALL-1 also acts at the stage of maintenance (Yu et al, 1998). Since considerably more genetic and biological information is available about TRX, in comparison to ALL-1, here we will emphasise studies of the former.…”