Polycomb group protein Mel18 inhibits hematopoietic stem cell self-renewal through repressing the transcription of self-renewal and proliferation genes.

Polycomb group (PcG) proteins play important roles in hematopoietic stem cell (HSC) self-renewal. Mel18 and Bmi1 are homologs of the PCGF subunit within the Polycomb repressive complex 1 (PRC1). Bmi1 (PCGF4) enhances HSC self-renewal and promotes terminal differentiation.

Cell-fate conversion of intestinal cells in adult Drosophila midgut by depleting a single transcription factor.

The manipulation of cell identity by reprograming holds immense potential in regenerative medicine, but is often limited by the inefficient acquisition of fully functional cells. This problem can potentially be resolved by better understanding the reprogramming process using in vivo genetic models, which are currently scarce. Here we report that both enterocytes (ECs) and enteroendocrine cells (EEs) in adult Drosophila midgut show a surprising degree of cell plasticity.

A hierarchical transcription factor cascade regulates enteroendocrine cell diversity and plasticity in Drosophila.

Enteroendocrine cells (EEs) represent a heterogeneous cell population in intestine and exert endocrine functions by secreting a diverse array of neuropeptides. Although many transcription factors (TFs) required for specification of EEs have been identified in both mammals and Drosophila, it is not understood how these TFs work together to generate this considerable subtype diversity. Here we show that EE diversity in adult Drosophila is generated via an "additive hierarchical TF cascade".

Identification of progenitor cells and their progenies in adult Drosophila midgut.

The intestinal epithelium in the anterior and posterior of the Drosophila midgut, which is maintained by intestinal stem cells (ISCs), represents a genetic tractable system for the study of stem cell biology, epithelial homeostasis and intestinal physiology and function. The ISCs self-renew and periodically generate absorptive enterocyte (EC) and secretory enteroendocrine cell (EE) via a committed progenitor stage termed as enteroblast (EB) or enteroendocrine progenitor (EEP), respectively. The progenitors in adult midgut are commonly referred to as all of the undifferentiated cells, including ISCs, EBs and EEPs.

Bmi1 Regulates Wnt Signaling in Hematopoietic Stem and Progenitor Cells.

Polycomb group protein Bmi1 is essential for hematopoietic stem cell (HSC) self-renewal and terminal differentiation. However, its target genes in hematopoietic stem and progenitor cells are largely unknown. We performed gene expression profiling assays and found that genes of the Wnt signaling pathway are significantly elevated in Bmi1 null hematopoietic stem and progenitor cells (HSPCs).

The specification and function of enteroendocrine cells in Drosophila and mammals: a comparative review.

Enteroendocrine cells (EECs) in both invertebrates and vertebrates derive from intestinal stem cells (ISCs) and are scattered along the digestive tract, where they function in sensing various environmental stimuli and subsequently secrete neurotransmitters or neuropeptides to regulate diverse biological and physiological processes. To fulfill these functions, EECs are specified into multiple subtypes that occupy specific gut regions. With advances in single-cell technology, organoid culture experimental systems, and CRISPR/Cas9-mediated genomic editing, rapid progress has been made toward characterization of EEC subtypes in mammals.

MRISCs protect colonic stem cells from inflammatory damage.

Increasing evidence suggest functional roles of subepithelial mesenchymal niche cells in maintaining intestinal stem cells and in modulating the pathogenesis of various intestinal diseases in mammals. A recent study reported the discovery of a new population of stromal cells in mice termed MAP3K2-Regulated Intestinal Stromal Cells (MRISCs); these cells reside at the base of colonic crypt and function to protect colonic stem cells during colonic inflammation by expressing the Wnt agonist R-spondin1 (Rspo1).

The cellular niche for intestinal stem cells: a team effort.

The rapidly self-renewing epithelium in the mammalian intestine is maintained by multipotent intestinal stem cells (ISCs) located at the bottom of the intestinal crypt that are interspersed with Paneth cells in the small intestine and Paneth-like cells in the colon. The ISC compartment is also closely associated with a sub-epithelial compartment that contains multiple types of mesenchymal stromal cells. With the advances in single cell and gene editing technologies, rapid progress has been made for the identification and characterization of the cellular components of the niche microenvironment that is essential for self-renewal and differentiation of ISCs.

A Progressive Somatic Cell Niche Regulates Germline Cyst Differentiation in the Drosophila Ovary.

In the germarium of the Drosophila ovary, developing germline cysts are surrounded by a population of somatic escort cells that are known to function as the niche cells for germline differentiation; however, the underlying molecular mechanisms of this niche function remain poorly understood. Through single-cell gene expression profiling combined with genetic analyses, we here demonstrate that the escort cells can be spatially and functionally divided into two successive domains. The anterior escort cells (aECs) specifically produce ecdysone, which acts on the cystoblast to promote synchronous cell division, whereas the posterior escort cells (pECs) respond to ecdysone signaling and regulate soma-germline cell adhesion to promote the transition from 16-cell cyst-to-egg chamber formation.

The Drosophila Ortholog of Mammalian Transcription Factor Sox9 Regulates Intestinal Homeostasis and Regeneration at an Appropriate Level.

Balanced stem cell self-renewal and differentiation is essential for maintaining tissue homeostasis, but the underlying mechanisms are poorly understood. Here, we identified the transcription factor SRY-related HMG-box (Sox) 100B, which is orthologous to mammalian Sox8/9/10, as a common target and central mediator of the EGFR/Ras and JAK/STAT signaling pathways that coordinates intestinal stem cell (ISC) proliferation and differentiation during both normal epithelial homeostasis and stress-induced intestinal repair in Drosophila. The two stress-responsive pathways directly regulate Sox100B transcription via two separate enhancers.

Bmi1 Maintains the Self-Renewal Property of Innate-like B Lymphocytes.

The self-renewal ability is a unique property of fetal-derived innate-like B-1a lymphocytes, which survive and function without being replenished by bone marrow (BM) progenitors. However, the mechanism by which IgM-secreting mature B-1a lymphocytes self-renew is poorly understood. In this study, we showed that was critically involved in this process.

A Switch in Tissue Stem Cell Identity Causes Neuroendocrine Tumors in Drosophila Gut.

Intestinal stem cells (ISCs) are able to generate gut-specific enterocytes, as well as neural-like enteroendocrine cells. It is unclear how the tissue identity of the ISC lineage is regulated to confer cell-lineage fidelity. Here, we show that, in adult Drosophila midgut, loss of the transcriptional repressor Tramtrack in ISCs causes a self-renewal program switch to neural stem cell (NSC)-like, and that switch drives neuroendocrine tumor development.

The Cellular Diversity and Transcription Factor Code of Drosophila Enteroendocrine Cells.

Enteroendocrine cells (EEs) in the intestinal epithelium have important endocrine functions, yet this cell lineage exhibits great local and regional variations that have hampered detailed characterization of EE subtypes. Through single-cell RNA-sequencing analysis, combined with a collection of peptide hormone and receptor knockin strains, here we provide a comprehensive analysis of cellular diversity, spatial distribution, and transcription factor (TF) code of EEs in adult Drosophila midgut. We identify 10 major EE subtypes that totally produced approximately 14 different classes of hormone peptides.

Division of Labor: Roles of Groucho and CtBP in Notch-Mediated Lateral Inhibition that Controls Intestinal Stem Cell Differentiation in Drosophila.

Intestinal stem cell (ISC) differentiation in the Drosophila midgut requires Delta/Notch-mediated lateral inhibition, which separates the fate of ISCs from differentiating enteroblasts (EBs). Although a canonical Notch signaling cascade is involved in the lateral inhibition, its regulation at the transcriptional level is still unclear. Here we show that the establishment of lateral inhibition between ISC-EB requires two evolutionarily conserved transcriptional co-repressors Groucho (Gro) and C-terminal binding protein (CtBP) that act differently.

Pelota-interacting G protein Hbs1 is required for spermatogenesis in Drosophila.

Hbs1, which is homologous to the GTPase eRF3, is a small G protein implicated in mRNA quality control. It interacts with a translation-release factor 1-like protein Dom34/Pelota to direct decay of mRNAs with ribosomal stalls. Although both proteins are evolutionarily conserved in eukaryotes, the biological function of Hbs1 in multicellular organisms is yet to be characterized.

Ovaries absent links dLsd1 to HP1a for local H3K4 demethylation required for heterochromatic gene silencing.

Unlabelled: Heterochromatin Protein 1 (HP1) is a conserved chromosomal protein in eukaryotic cells that has a major role in directing heterochromatin formation, a process that requires co-transcriptional gene silencing mediated by small RNAs and their associated argonaute proteins. Heterochromatin formation requires erasing the active epigenetic mark, such as H3K4me2, but the molecular link between HP1 and H3K4 demethylation remains unclear. In a fertility screen in female , we identified (), which functions in the stem cell niche, downstream of Piwi, to support germline stem cell differentiation.

Probing the Function of Metazoan Histones with a Systematic Library of H3 and H4 Mutants.

Replication-dependent histone genes often reside in tandemly arrayed gene clusters, hindering systematic loss-of-function analyses. Here, we used CRISPR/Cas9 and the attP/attB double-integration system to alter numbers and sequences of histone genes in their original genomic context in Drosophila melanogaster. As few as 8 copies of the histone gene unit supported embryo development and adult viability, whereas flies with 20 copies were indistinguishable from wild-types.

Correction: Tumor driven by gain-of-function HER2 H878Y mutant is highly sensitive to HER2 inhibitor.

[This corrects the article DOI: 10.18632/oncotarget.5221.

Author Correction: Transient Scute activation via a self-stimulatory loop directs enteroendocrine cell pair specification from self-renewing intestinal stem cells.

In the version of this Article originally published, the author had misnumbered the reference citations in the Methods, using numbers 1-14 instead of 46-59. These errors have now been corrected in all online versions of the Article.

Transient Scute activation via a self-stimulatory loop directs enteroendocrine cell pair specification from self-renewing intestinal stem cells.

The process through which multiple types of cell-lineage-restricted progenitor cells are specified from multipotent stem cells is unclear. Here we show that, in intestinal stem cell lineages in adult Drosophila, in which the Delta-Notch-signalling-guided progenitor cell differentiation into enterocytes is the default mode, the specification of enteroendocrine cells (EEs) is initiated by transient Scute activation in a process driven by transcriptional self-stimulation combined with a negative feedback regulation between Scute and Notch targets. Scute activation induces asymmetric intestinal stem cell divisions that generate EE progenitor cells.

A Phyllopod-Mediated Feedback Loop Promotes Intestinal Stem Cell Enteroendocrine Commitment in Drosophila.

The intestinal epithelium in the Drosophila midgut is maintained by intestinal stem cells (ISCs), which are capable of generating both enterocytes and enteroendocrine cells (EEs) via alternative cell fate specification. Activation of Delta-Notch signaling directs ISCs for enterocyte generation, but how EEs are generated from ISCs remains poorly understood. Here, we identified Phyllopod (Phyl) as a key regulator that drives EE generation from ISCs.

Mrg15 stimulates Ash1 H3K36 methyltransferase activity and facilitates Ash1 Trithorax group protein function in Drosophila.

Ash1 is a Trithorax group protein that possesses H3K36-specific histone methyltransferase activity, which antagonizes Polycomb silencing. Here we report the identification of two Ash1 complex subunits, Mrg15 and Nurf55. In vitro, Mrg15 stimulates the enzymatic activity of Ash1.

BMI1 and MEL18 Promote Colitis-Associated Cancer in Mice via REG3B and STAT3.

Background & Aims: Polycomb group proteins are epigenetic factors that silence gene expression; they are dysregulated in cancer cells and contribute to carcinogenesis by unclear mechanisms. We investigated whether BMI1 proto-oncogene, polycomb ring finger (BMI1), and polycomb group ring finger 2 (PCGF2, also called MEL18) are involved in the initiation and progression of colitis-associated cancer (CAC) in mice.

Methods: We generated mice containing floxed alleles of Bmi1 and/or Mel18 and/or Reg3b using the villin-Cre promoter (called Bmi1, Mel18, DKO, and TKO mice).

Transcription Factor Antagonism Controls Enteroendocrine Cell Specification from Intestinal Stem Cells.

The balanced maintenance and differentiation of local stem cells is required for Homeostatic renewal of tissues. In the Drosophila midgut, the transcription factor Escargot (Esg) maintains undifferentiated states in intestinal stem cells, whereas the transcription factors Scute (Sc) and Prospero (Pros) promote enteroendocrine cell specification. However, the mechanism through which Esg and Sc/Pros coordinately regulate stem cell differentiation is unknown.