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We characterized the mouse ortholog of the human MLL3 gene and a 10.6 kb-Mll3 transcript. The mouse Mll3 gene comprises 60 exons that encompass 226 kb in chromosome 5. The predicted protein of 3464 amino acids contains two PHD domains, an ATPase alpha_beta signature, an HMG, and a SET domain. We analyzed the expression of the Mll3 gene during the embryonic development of the mouse by whole-mount in situ hybridization. Low levels of expression throughout the embryo were first detected at 8.0 dpc. At this stage, the signal was already stronger in the forebrain neuroepithelium and absent in the heart. Next, expression outlined the ventral neural tube, the somites, the limbs, and the eye lens remaining at low levels throughout the embryo. By 13.0 dpc, expression became stronger in the spinal cord, in hand/foot plates, and in gonads. RT-PCR confirmed that Mll3 is expressed early during gametogenesis. We suggest that Mll3 is expressed early in pre-spermatogonia and then in spermatogonia.

We have analysed the genomic structure and transcriptional activity of a 2.3-Mb genomic sequence in the juxtacentromeric region of human chromosome 21. Our work shows that this region comprises two different chromosome domains. The 1.5-Mb proximal domain: (i) is a patchwork of chromosome duplications; (ii) shares sequence similarity with several chromosomes; (iii) contains several gene fragments (truncated genes having an intron/exon structure) intermingled with retrotransposed pseudogenes; and (iv) harbours two genes (TPTE and BAGE2) that belong to gene families and have a cancer and/or testis expression profile. The TPTE gene family was generated before the branching of Old World monkeys from the great ape lineage, by intra- and interchromosome duplications of the ancestral TPTE gene mapping to phylogenetic chromosome XIII. By contrast, the 0.8-Mb distal domain: (i) is devoid of chromosome duplications; (ii) has a chromosome 21-specific sequence; (iii) contains no gene fragments and only one retrotransposed pseudogene; and (iv) harbours six genes including housekeeping genes. G-rich sequences commonly associated with duplication termini cluster at the boundary between the two chromosome domains. These structural and transcriptional features lead us to suggest that the proximal domain has heterochromatic properties, whereas the distal domain has euchromatic properties.

We characterized MLL3, a new human member of the TRX/MLL gene family. MLL3 is expressed in peripheral blood, placenta, pancreas, testes, and foetal thymus and is weakly expressed in heart, brain, lung, liver, and kidney. It encodes a predicted protein of 4911 amino acids containing two plant homeo domains (PHD), an ATPase alpha_beta signature, a high mobility group, a SET (Suppressor of variegation, Enhancer of zeste, Trithorax) and two FY (phenylalanine tyrosine)-rich domains. The amino acid sequence of the SET domain was used to obtain a phylogenetic tree of human MLL genes and their homologues in different species. MLL3 is closely related to human MLL2, Fugu mll2, a Caenorhabditis elegans predicted protein, and Drosophila trithorax-related protein. Interestingly, PHD and SET domains are frequently found in proteins encoded by genes that are rearranged in different haematological malignancies and MLL3 maps to 7q36, a chromosome region that is frequently deleted in myeloid disorders. Partial duplications of the MLL3 gene are found in the juxtacentromeric region of chromosomes 1, 2, 13, and 21.