Stem Cell Proliferation Is Kept in Check by the Chromatin Regulators Kismet/CHD7/CHD8 and Trr/MLL3/4

摘要

class="head no_bottom_margin" id="sec1title">IntroductionRegulation of stem cell proliferation rates is critical in adult tissues, which need to maintain basal renewal and undergo damage-induced regenerative responses. Consequently, the dysregulation of stem cell proliferation can have pathological effects. Ample evidence now supports a functional link between the deregulated proliferation of stem cells and cancer initiation, as well as metastatic progression (, ). Interestingly, the loss of epigenetic control is a major contributor to stem cell misregulation including proliferation deregulation during aging (, , ). Therefore, in addition to roles of epigenetic regulation during differentiation of stem-cell-derived lineages, chromatin modulation also has important, though not yet well understood, roles in the control of stem cell proliferation.A useful model to investigate adult stem cell regulation is the Drosophila midgut, which is maintained by around 1,000 multipotent intestinal stem cells (ISCs). Most ISC divisions lead to asymmetric daughter cell fates, resulting in a self-renewed ISC and a sister enteroblast (EB) cell (A). A majority of EBs receive high levels of Notch signaling and differentiate into enterocyte cells (ECs). Rare stem cell divisions produce an enteroendocrine precursor cell (EEP) with low or no Notch signaling, which is thought to divide once to make two enteroendocrine cells (EEs) (, , ). In response to epithelial damage, several signaling pathways become activated and coordinate ISC proliferation and differentiation (see for review, ). Of primary importance are signals that the ISCs receive to activate the Jak/Stat and Epidermal Growth Factor Receptor (EGFR) pathways (, , , , , href="#bib113" rid="bib113" class=" bibr popnode">Wang et al., 2014, href="#bib114" rid="bib114" class=" bibr popnode">Xu et al., 2011). Moreover, other pathways such as Insulin, Hippo, Jun Kinase, BMP, Wnt, and Hedgehog also control ISC proliferation (href="#bib7" rid="bib7" class=" bibr popnode">Biteau et al., 2008, href="#bib19" rid="bib19" class=" bibr popnode">Cordero et al., 2012, href="#bib58" rid="bib58" class=" bibr popnode">Li et al., 2013, href="#bib59" rid="bib59" class=" bibr popnode">Li et al., 2014, href="#bib60" rid="bib60" class=" bibr popnode">Lin et al., 2008, href="#bib75" rid="bib75" class=" bibr popnode">O'Brien et al., 2011, href="#bib86" rid="bib86" class=" bibr popnode">Ren et al., 2010, href="#bib96" rid="bib96" class=" bibr popnode">Shaw et al., 2010, href="#bib101" rid="bib101" class=" bibr popnode">Staley and Irvine, 2010, href="#bib107" rid="bib107" class=" bibr popnode">Tian and Jiang, 2014, href="#bib108" rid="bib108" class=" bibr popnode">Tian et al., 2015, href="#bib109" rid="bib109" class=" bibr popnode">Tian et al., 2017). Evidence suggests that there are also mechanisms to limit ISC responsiveness, tuning down cell division when sufficient renewal has occurred (href="#bib37" rid="bib37" class=" bibr popnode">Guo et al., 2013, href="#bib43" rid="bib43" class=" bibr popnode">Hochmuth et al., 2011), though this process is not well understood.href="/pmc/articles/PMC6547167/figure/fig1/" target="figure" rid-figpopup="fig1" rid-ob="ob-fig1">class="inline_block ts_canvas" href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Click%20on%20image%20to%20zoom&p=PMC3&id=6547167_gr1.jpg" target="tileshopwindow">target="object" href="/pmc/articles/PMC6547167/figure/fig1/?report=objectonly">Open in a separate windowclass="figpopup" href="/pmc/articles/PMC6547167/figure/fig1/" target="figure" rid-figpopup="fig1" rid-ob="ob-fig1">Figure 1Loss of kismet Provokes ISC Accumulation without Affecting Terminal Differentiation(A) The ISCs divide to self-renew and to produce a precursor cell, the EB, that subsequently terminally differentiates into an EC or is thought to divide once as an EEP to produce two EE cells.(B and C) Wild-type (B) and kis^10D26 mutant (C) MARCM clones, 5 days after heat shock (AHS).(D) Quantification of (B) and (C).(E) Scheme of wild-type and kismet mutant clones.(F) Scheme of kismet gene and Kismet protein (Long and short isoforms: Kis L and Kis S): chromodomains (green), ATPase domain (red), BRK domain (blue). All kis alleles resulted in nonsense mutations: nucleotide changes and corresponding putative resulting truncated proteins are shown.(G–L) Wild-type and kis^10D26 MARCM clones at 9 days AHS. Arrows in (G)–(H′) and (I)–(J′) show EE cells marked by DH31 or LTK2, respectively.(M–P) Quantification of the total cells per clone (M), number of EE cells per clone (Prospero+) (N), number of ECs (Pdm1+ cells per clone) (O), and the ratio of EE (Prospero+ cells / EC (polyploid nucleus >7 μm) per clone (P).(Q and R) Vertical sections through the midgut epithelium of control (Q) and kis^10D26 mutant (R) MARCM clones, 9 days AHS. Arrows show apical membrane.In (D) and (M)–(P), A two-tailed Mann-Whitney statistical test was used; mean values in red; error bars, SEM; ns = non-significant, **p < 0.01, ****p < 0.0001. Scale bars, 20 μm.