The relationship between Mll1 and Notch signaling in epithelial stem cell homeostasis
Final Report Abstract
Trimethylation of histone H3 lysine 4 (H3K4me3) at the promoters of actively transcribed genes is a universal epigenetic mark and a key product of Trithorax group action. Mammals have two trithorax homologs, Mll1 and Mll2, having arisen from gene duplication. Both proteins are very large and share the same architecture. Despite the high similarity, only MLL has been described to date as a protooncogene that can be activated by chromosomal translocations. Mll1 is required for hematopoietic stem cell development and maintenance. However, its role in nonhematopoietic tissues still remains enigmatic. The functional relationship between Mll1 and Mll2 is not known. We wanted to determine whether Mll1 and Mll2 encompass redundant functions during development and in adult mice. Therefore we created multipurpose alleles for both Mll1 and Mll2. By conversion of the alleles from one state to another, we established the null phenotypes in mouse development and in embryonic stem cells. Our research led to four main findings. i) Both Mll1 and Mll2 are required in the hematopoietic compartment. To determine the role of Mll1 during adult steady-state hematopoiesis, we were using tamoxifen-induced conditional mutagenesis. Cre-mediated ablation of Mll1 causes a severe bone marrow cytopenia and death within 3 weeks. Mll1 deletion results in a decreased KLS population reflecting the hematopoietic stem cell enriched population. Additional removal of Mll2 leads to no further impairment of the described bone marrow defects. Surprisingly the Mll2 deleted mice developed splenomegaly and myeloid neoplasia with increasing age. ii) Both Mll1 and Mll2 are required for memory consolidation. Mll1 cKO and Mll2 cKO mice display severe defects in memory consolidation. To elucidate the mechanisms by which Mll1 and Mll2 contribute to hippocampusdependent memory formation we analyzed gene expression in the hippocampal formation. Deletion of Mll2 causes downregulation of many genes linked to memory function and synaptic plasticity. Genes deregulated after loss Mll1 are entirely different and fall into entirely different functional categories. iii) In mouse embryonic stem cells Mll1 plays a partially redundant role to Mll2 on active promoters. Bivalent promoters rely on Mll2 for H3K4me3 whereas active promoters have more than one bound H3K4methyltransferase. Removal of Mll1, sister to Mll2, had almost no effect on any promoter unless Mll2 was also removed, indicating functional backup between these enzymes. iiii) Mll1 is essential for the maintenance of the crypt compartment of the small intestine. Loss of Mll1 protein is lethal in adults owing to a rapid failure of intestinal functions. The main defects are a distortion of the differentiated linages and a substantial reduction in stem cells in the small intestine. Together, these findings unravel a key role of the H3K4 methyltransferase Mll1 to maintain the intestinal stem cells and therefore to control the homeostasis of adult intestine.
Publications
- (2013). Histone-methyltransferase MLL2 (KMT2B) is required for memory formation in mice. The Journal of Neuroscience 33(8): 3452-3464
Kerimoglu C, Agis-Balboa RC, Kranz A, Stilling R, Bahari-Javan S, Benito-Garagorri E, Halder R, Burkhardt S, Stewart AF, Fischer A
(See online at https://doi.org/10.1523/JNEUROSCI.3356-12.2013) - (2014). Mll2 is required for H3K4 trimethylation on bivalent promoters in embryonic stem cells, whereas Mll1 is redundant. Development 141(3): 526-37
Denissov S, Hofemeister H, Marks H, Kranz A, Ciotta G, Singh S, Anastassiadis K, Stunnenberg HG, Stewart AF
(See online at https://doi.org/10.1242/dev.102681)
