MLL4 is required after implantation whereas MLL3 becomes essential during late gestation

Abstract

Methylation of histone 3 lysine 4 (H3K4) is a major epigenetic system associated with gene expression. In mammals there are six H3K4 methyltransferases related to yeast Set1 and fly Trithorax, including two orthologs of fly Trithorax-related: MLL3 and MLL4. Exome sequencing has documented high frequencies of MLL3 and MLL4 mutations in many types of human cancer. Despite this emerging importance, the requirements of these paralogs in mammalian development have only been incompletely reported. Here, we examined the null phenotypes to establish that MLL3 is first required for lung maturation, whereas MLL4 is first required for migration of the anterior visceral endoderm that initiates gastrulation in the mouse. This collective cell migration is preceded by a columnar-to-squamous transition in visceral endoderm cells that depends on MLL4. Furthermore, Mll4 mutants display incompletely penetrant, sexdistorted, embryonic haploinsufficiency and adult heterozygous mutants show aspects of Kabuki syndrome, indicating that MLL4 action, unlike MLL3, is dosage dependent. The highly specific and discordant functions of these paralogs in mouse development argues against their action as general enhancer factors.

Kmt2c mutations enhance HSC self-renewal capacity and convey a selective advantage after chemotherapy

“…This mutation caused complete loss of protein expression (Figure 1B). Kmt2c À/À mice died at birth yet appeared morphologically normal, consistent with prior studies in which an exon 49 deletion or an intron 33 gene trap insertion led to pulmonary failure and perinatal lethality (Ashokkumar et al, 2020;Lee et al, 2013). We measured HSC numbers (CD150 + CD48 À Lineage À c-kit + Sca1 + ; Figure S1A) in wild-type, Kmt2c +/À , and Kmt2c À/À embryonic day (E) 18.5 fetal mice and in wild-type and Kmt2c +/À 8-week-old adult mice.…”

MLL3/MLL4 Histone Methyltranferase Activity Dependent Chromatin Organization at Enhancers during Embryonic Stem Cell Differentiation

“…MLL3/4 play crucial roles in mammalian development. Mll4 knockout in mice leads to embryonic lethality (Ashokkumar et al, 2020; Lee et al, 2013), and development of heart, adipose, muscle, and immune cells is severely impeded after Mll3/4 depletion (Ang et al, 2016; Lee et al, 2013; Placek et al, 2017). Furthermore, mutations in MLL3/4 genes are frequently observed in human cancers and developmental disorders (Ng et al, 2010; Parsons et al, 2011; Pasqualucci et al, 2011; Sze and Shilatifard, 2016; Will and Steidl, 2014).…”

MLL3/MLL4 methyltransferase activities control early embryonic development and embryonic stem cell differentiation in a lineage-selective manner

“…and display a defect in anterior VE migration precedes gastrulation 4,7 . The phenotypes of Mll3 KI/KI and Mll4 KI/KI mice are much alleviated.…”

“…MLL3 and MLL4 (MLL3/4) are members of the Set1-like family of mammalian H3K4 methyltransferases that are responsible for catalyzing H3K4me1 4 . They are the largest known nuclear proteins (4,903 and 5,588 amino acids in mice, respectively), and associate with the WRAD (WDR5, RbBP5, ASH2L, DPY30) subcomplex as well as NCOA6, UTX, PA1, and PTIP in a large multi-subunit complex 7,8 .…”