MOF Histone Acetyltransferase in Blood Cell Development
Authors: Yasmin Serina Secanechia, Christophe Lancrin
Journal: Trends in Genetics (2020)

Gene expression is regulated by transcription factors (TFs) and chromatin modifiers such as histone acetyltransferases (HATs). Pessoa Rodrigues et al. revealed the role of the Males absent on the first (MOF) HAT in hematopoietic stem cell (HSC) differentiation into red blood cells. This work raises interesting questions about how MOF controls other hematopoietic differentiation processes. Gene expression is regulated by transcription factors (TFs) and chromatin modifiers such as histone acetyltransferases (HATs). Pessoa Rodrigues et al. revealed the role of the Males absent on the first (MOF) HAT in hematopoietic stem cell (HSC) differentiation into red blood cells. This work raises interesting questions about how MOF controls other hematopoietic differentiation processes. The human body contains hundreds of cell types. The difference in cell identity is finely regulated by how TFs activate or repress specific sets of genes [1.Bergiers I. et al.Single-cell transcriptomics reveals a new dynamical function of transcription factors during embryonic hematopoiesis.Elife. 2018; 7e29312Crossref PubMed Scopus (15) Google Scholar]. Another level of gene regulation is directly related to how accessible a certain region of the genome is. DNA is wrapped around proteins called histones forming chromatin, whose level of compaction directly affects the ability of a given TF to bind its target genes. This is controlled by post-transcriptional modifications of the histones, such as phosphorylation, methylation, ubiquitination, and acetylation [2.Lawrence M. et al.Lateral thinking: how histone modifications regulate gene expression.Trends Genet. 2015; 32: 42-56Abstract Full Text Full Text PDF PubMed Scopus (350) Google Scholar]. For instance, histone acetylation is linked to decompaction of the chromatin, making the transcriptional activation of given genes possible. All histones of the nucleosome (the basic chromatin subunit) can be acetylated at specific lysine residues (Figure 1A ). An interesting example is the lysine at position 16 of histone H4. The addition of an acetyl group on this lysine has a direct impact on the structure of the chromatin by making it less compact (reviewed in [3.Rea S. et al.Males absent on the first (MOF): from flies to humans.Oncogene. 2007; 26: 5385-5394Crossref PubMed Scopus (100) Google Scholar]). The HAT MOF (also known as KAT8) is the main enzyme responsible for the acetylation of histone H4 at lysine 16. This modification is reversible and can be removed by histone deacetylases (HDACs) (Figure 1B). MOF was first described in Drosophila where it plays a role in equalizing X-linked gene expression between male and female flies [3.Rea S. et al.Males absent on the first (MOF): from flies to humans.Oncogene. 2007; 26: 5385-5394Crossref PubMed Scopus (100) Google Scholar]. It has since been shown that MOF is highly conserved from fly to mammalian species (reviewed in [4.Sheikh B.N. et al.The non-specific lethal (NSL) complex at the crossroads of transcriptional control and cellular homeostasis.EMBO Rep. 2019; 20e47630Crossref PubMed Scopus (15) Google Scholar]), suggesting important functions across evolution. As in Drosophila, mammalian MOF is a member of two chromatin remodeling complexes: the male-specific lethal (MSL) complex and the nonspecific lethal (NSL) (KANSL in mammals) complex [4.Sheikh B.N. et al.The non-specific lethal (NSL) complex at the crossroads of transcriptional control and cellular homeostasis.EMBO Rep. 2019; 20e47630Crossref PubMed Scopus (15) Google Scholar]. The importance of MOF in mammalian biology was further supported by the incapacity of Mof-knockout mice to complete embryogenesis [5.Gupta A. et al.The mammalian ortholog of Drosophila MOF that acetylates histone H4 lysine 16 is essential for embryogenesis and oncogenesis.Mol. Cell. Biol. 2008; 28: 397-409Crossref PubMed Scopus (163) Google Scholar]. Due to the embryonic lethality of the Mof knockout, researchers had to rely on conditional loss-of-function tools and on heterozygous Mof mouse mutants to study its role in adult tissues. Using these animal models, Pessoa Rodrigues et al. explored the role of MOF in hematopoiesis, the process of blood cell formation. This process ensures the daily generation of billions of cells to allow the oxygenation of tissues, to mediate defense against pathogens, and to stop bleeding in the body. Using transcriptome analysis, Pessoa Rodrigues et al. [6.Pessoa Rodrigues C. et al.Temporal expression of MOF acetyltransferase primes transcription factor networks for erythroid fate.Sci. Adv. 2020; 6eaaz4815Crossref Scopus (7) Google Scholar] found that MOF was preferentially expressed in HSCs and megakaryocyte-erythroid progenitors (MEPs), which eventually generate red blood cells. By investigating the effects of MOF loss of function on mouse hematopoiesis in vivo and ex vivo, the authors identified a role for MOF, as part of the NSL complex, in the earlier stages of erythropoiesis. Using a method to measure chromatin accessibility called assay of transposase-accessible chromatin with visualization (ATAC-see), the authors could identify a global reduction in chromatin accessibility in HSCs and MEPs in Mof+/− compared with wild-type (WT) mice. This is suggestive of a link between chromatin accessibility and H4K16 acetylation level. Hematopoietic functional assays in vitro and in vivo also showed that this reduction in chromatin accessibility was linked to a dramatic reduction of red blood cell production. To gain a mechanistic understanding of MOF's role in erythropoiesis, the authors assessed the binding of MOF to the chromatin of HSCs and MEPs from WT and Mof+/− mice by ChIP-seq. Their result indicated that the binding of MOF in HSCs and MEPs mediates an increase in chromatin accessibility, which directs erythroid fate. Interestingly, among the MOF-bound genes they found in HSC was Runx1, a known regulator of HSC differentiation. They showed that RUNX1 induced the expression of another TF called GFI1B. The latter was shown to be a regulator of MOF in the MEPs, ensuring an appropriate level of chromatin accessibility for successful erythropoiesis. This elegant study demonstrated how proper dosage and timing of MOF activity could impact erythroid cell fate commitment through H4K16ac-driven chromatin accessibility. As expected, new questions emerge from this exciting body of work. One relates to the expression of Mof in HSCs and, more specifically, what drives it. As GFI1B is not yet expressed at this stage, other TFs must be responsible for the expression of Mof in HSCs. Other outstanding questions concern the function of MOF in embryonic hematopoiesis. The process of hematopoiesis is as crucial during embryogenesis as it is in the adult stages. Indeed, it is during embryonic life that HSCs start to be produced. In a previous study, a conditional loss of function of Mof in embryonic hematopoietic cells was investigated. Interestingly, they did not notice any severe phenotypes in the embryo. What they observed was a failure of hematopoiesis in newborns with 100% lethality [7.Valerio D.G. et al.Histone acetyltransferase activity of MOF is required for adult but not early fetal hematopoiesis in mice.Blood. 2017; 129: 48-59Crossref PubMed Scopus (22) Google Scholar]. All tested blood lineages were reduced. There is a discrepancy between this work and that by Pessoa Rodrigues et al. This may be related to the stage at which the Mof gene was lost. Discovering where the difference comes from may help to reveal other facets of MOF's functions. Although MOF did not appear to play any major roles in embryonic blood development, Pessoa Rodrigues et al. used the embryonic hematopoietic cell line HPC7 to validate a number of their findings. This suggests that MOF could be active during embryonic hematopoiesis. RUNX1 and GFI1B are expressed during development, where they play important functions in the endothelial-to-hematopoietic transition (EHT) [8.Lancrin C. et al.GFI1 and GFI1B control the loss of endothelial identity of hemogenic endothelium during hematopoietic commitment.Blood. 2012; 120: 314-322Crossref PubMed Scopus (95) Google Scholar]. This process involves a dramatic change in cell identity and is absolutely required for the formation of HSCs. There is evidence that histone post-translational modifications play a role in the EHT (reviewed in [9.Thambyrajah R. et al.New insights into the regulation by RUNX1 and GFI1(s) proteins of the endothelial to hematopoietic transition generating primordial hematopoietic cells.Cell Cycle. 2016; 15: 2108-2114Crossref PubMed Scopus (14) Google Scholar]). However, to date no one has analyzed the dynamics of H4K16 acetylation in this context, although there is evidence of Mof gene expression in embryonic endothelial cells [10.Oatley M. et al.Single-cell transcriptomics identifies CD44 as a marker and regulator of endothelial to haematopoietic transition.Nat. Commun. 2020; 11: 586Crossref PubMed Scopus (23) Google Scholar]. Assessing the effect of MOF loss in the embryonic endothelium could reveal novel functions of this chromatin modifier beyond steady-state hematopoiesis.