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PubMed1998

A proline-rich region in the Zeste protein essential for transvection and white repression by Zeste.

The DNA-binding protein encoded by the zeste gene of Drosophila activates transcription and mediates interchromosomal interactions such as transvection. The mutant protein encoded by the zeste1 (z1) allele retains the ability to support transvection, but represses white. Similar to transvection, repression requires Zeste-Zeste protein interactions and a second copy of white, either on the homologous chromosome or adjacent on the same chromosome. We characterized two pseudorevertants of z1 (z1-35 and z1-42) and another zeste mutation (z78c) that represses white. The z1 lesion alters a lysine residue located between the N-terminal DNA-binding domain and the C-terminal hydrophobic repeats involved in Zeste self-interactions. The z78c mutation alters a histidine near the site of the z1 lesion. Both z1 pseudorevertants retain the z1 lesion and alter different prolines in a proline-rich region located between the z1 lesion and the self-interaction domain. The pseudorevertants retain the ability to self-interact, but fail to repress white or support transvection at Ultrabithorax. To account for these observations and evidence indicating that Zeste affects gene expression through Polycomb group (Pc-G) protein complexes that epigenetically maintain chromatin states, we suggest that the regions affected by the z1, z78c, and pseudorevertant lesions mediate interactions between Zeste and the maintenance complexes.

ATP-Binding Cassette Transporters↗

PubMed2000

A genetic screen for zygotic embryonic lethal mutations affecting cuticular morphology in the wasp Nasonia vitripennis.

We have screened for zygotic embryonic lethal mutations affecting cuticular morphology in Nasonia vitripennis (Hymenoptera; Chalcidoidea). Our broad goal was to investigate the use of Nasonia for genetically surveying conservation and change in regulatory gene systems, as a means to understand the diversity of developmental strategies that have arisen during the course of evolution. Specifically, we aim to compare anteroposterior patterning gene functions in two long germ band insects, Nasonia and Drosophila. In Nasonia, unfertilized eggs develop as haploid males while fertilized eggs develop as diploid females, so the entire genome can be screened for recessive zygotic mutations by examining the progeny of F1 females. We describe 74 of >100 lines with embryonic cuticular mutant phenotypes, including representatives of coordinate, gap, pair-rule, segment polarity, homeotic, and Polycomb group functions, as well as mutants with novel phenotypes not directly comparable to those of known Drosophila genes. We conclude that Nasonia is a tractable experimental organism for comparative developmental genetic study. The mutants isolated here have begun to outline the extent of conservation and change in the genetic programs controlling embryonic patterning in Nasonia and Drosophila.

Animals↗

PubMed2000

Regulation of proboscipedia in Drosophila by homeotic selector genes.

The gene proboscipedia (pb) is a member of the Antennapedia complex in Drosophila and is required for the proper specification of the adult mouthparts. In the embryo, pb expression serves no known function despite having an accumulation pattern in the mouthpart anlagen that is conserved across several insect orders. We have identified several of the genes necessary to generate this embryonic pattern of expression. These genes can be roughly split into three categories based on their time of action during development. First, prior to the expression of pb, the gap genes are required to specify the domains where pb may be expressed. Second, the initial expression pattern of pb is controlled by the combined action of the genes Deformed (Dfd), Sex combs reduced (Scr), cap'n'collar (cnc), and teashirt (tsh). Lastly, maintenance of this expression pattern later in development is dependent on the action of a subset of the Polycomb group genes. These interactions are mediated in part through a 500-bp regulatory element in the second intron of pb. We further show that Dfd protein binds in vitro to sequences found in this fragment. This is the first clear demonstration of autonomous positive cross-regulation of one Hox gene by another in Drosophila melanogaster and the binding of Dfd to a cis-acting regulatory element indicates that this control might be direct.

Animals↗

PubMed2001

DSP1, an HMG-like protein, is involved in the regulation of homeotic genes.

The Drosophila dsp1 gene, which encodes an HMG-like protein, was originally identified in a screen for corepressors of Dorsal. Here we report that loss of dsp1 function causes homeotic transformations resembling those associated with loss of function in the homeotic genes Sex combs reduced (Scr), Ultrabithorax (Ubx), and Abdominal-B. The expression pattern of Scr is altered in dsp1 mutant imaginal discs, indicating that dsp1 is required for normal expression of this gene. Genetic interaction studies reveal that a null allele of dsp1 enhances trithorax-group gene (trx-G) mutations and partially suppresses Polycomb-group gene (Pc-G) mutations. On the contrary, overexpression of dsp1 induces an enhancement of the transformation of wings into halteres and of the extra sex comb phenotype of Pc. In addition, dsp1 male mutants exhibit a mild transformation of A4 into A5. Comparison of the chromatin structure at the Mcp locus in wild-type and dsp1 mutant embryos reveals that the 300-bp DNase I hypersensitive region is absent in a dsp1 mutant context. We propose that DSP1 protein is a chromatin remodeling factor, acting as a trx-G or a Pc-G protein depending on the considered function.

Alleles↗

PubMed2002

Regulation of larval hematopoiesis in Drosophila melanogaster: a role for the multi sex combs gene.

Drosophila larval hematopoietic organs produce circulating hemocytes that ensure the cellular host defense by recognizing and neutralizing non-self or noxious objects through phagocytosis or encapsulation and melanization. Hematopoietic lineage specification as well as blood cell proliferation and differentiation are tightly controlled. Mutations in genes that regulate lymph gland cell proliferation and hemocyte numbers in the body cavity cause hematopoietic organ overgrowth and hemocyte overproliferation. Occasionally, mutant hemocytes invade self-tissues, behaving like neoplastic malignant cells. Two alleles of the Polycomb group (PcG) gene multi sex combs (mxc) were previously isolated as such lethal malignant blood neoplasm mutations. PcG genes regulate Hox gene expression in vertebrates and invertebrates and participate in mammalian hematopoiesis control. Hence we investigated the need for mxc in Drosophila hematopoietic organs and circulating hemocytes. We show that mxc-induced hematopoietic hyperplasia is cell autonomous and that mxc mainly controls plasmatocyte lineage proliferation and differentiation in lymph glands and circulating hemocytes. Loss of the Toll pathway, which plays a similar role in hematopoiesis, counteracted mxc hemocyte proliferation but not mxc hemocyte differentiation. Several PcG genes tested in trans had no effects on mxc hematopoietic phenotypes, whereas the trithorax group gene brahma is important for normal and mutant hematopoiesis control. We propose that mxc provides one of the regulatory inputs in larval hematopoiesis that control normal rates of plasmatocyte and crystal lineage proliferation as well as normal rates and timing of hemocyte differentiation.

Animals↗

PubMed1973

Homoeosis in Drosophila. I. Complementation studies with revertants of Nasobemia.

A number of homoeotic mutants have been localized to the proximal right arm of chromosome 3 of Drosophila melanogaster. These include seven alleles of Antennapedia (Antp), which is associated with a transformation of antennae into legs; Nasobemia (Ns), which causes the same phenotype as Antp but was considered by Gehring (1966) not to be an allele; and three genes causing a transformation of second and third legs into first legs: Extra sex comb (Scx), Polycomb (Pc), and Multiple sex comb (Msc.). The alleles of Antp and Scx share a common recessive lethal effect, and Pc maps 0.2-0.3 units to the left of Scx.-In the present investigation, rearrangements associated with the reversion of Ns suggest that its cytological location is in or just distal to salivary chromosome doublet 84B1-2. Although Ns is viable when homozygous, four of its revertants share a common recessive lethal effect. These revertants fail to complement the recessive lethality of Antp(B) and Scx. Furthermore, they show a complex pattern of functional interaction with Pc and with Humeral (Hu), a dominant mutation associated with a rearrangement with one breakpoint just distal to 84B1-2. Finally, analysis of a revertant of Msc indicates that Msc is also located very close to 84B1-2. It is concluded that Ns and Scx are alleles of Antp. Pc shows many functional similarities to the Antp locus, but is probably not allelic. Evidence is presented that these dominant homoeotic genes are neomorphic in nature.

Animals↗

PubMed2005

Imprinted X inactivation and reprogramming in the preimplantation mouse embryo.

X chromosome inactivation is a developmentally regulated process that causes one of the two X chromosomes in normal female mammals to become transcriptionally silenced, thus equalizing the expression of X-linked genes between the sexes. Such dosage compensation depends upon dynamic genetic and epigenetic events occurring very early in development. X inactivation is controlled by an X inactivation centre that is associated with the expression of non-coding RNAs required for the silencing. Also associated with the inactive X are repressive histone modifications and polycomb protein-mediated states, which are progressively acquired during the inactivation process. In mouse, two forms of X inactivation have been described. Random X inactivation happens in the derivatives of the inner cell mass (ICM) giving rise to embryos where the maternally inherited X(Xm) is inactive in some cells and the paternally derived X (Xp) is inactive in others. Random X inactivation occurs around the time of implantation. Imprinted X inactivation, the preferential inactivation of the Xp chromosome, occurs earlier and, although there has been some debate as to the precise timing of initiation of this event, is apparent in all cells early in preimplantation development, then is subsequently confined to the cells of the extraembryonic lineages. A picture is emerging whereby initial epigenetic asymmetry between the two parental X chromosomes is reprogrammed in a lineage specific manner resulting in a switch from imprinted to random inactivation in embryonic derivatives. Neither the underlying reason nor the full extent of these early lineage specific epigenetic changes is known, but they may be correlated with more genome-wide reprogramming events essential for normal development.

Alleles↗

PubMed2006

Maintenance of X- and Y-inactivation of the pseudoautosomal (PAR2) gene SPRY3 is independent from DNA methylation and associated to multiple layers of epigenetic modifications.

Maintenance of X-inactivation is achieved through a combination of different repressive mechanisms, thus perpetuating the silencing message through many cell generations. The second human X-Y pseudoautosomal region 2 (PAR2) is a useful model to explore the features and internal relationships of the epigenetic circuits involved in this phenomenon. Recently, we demonstrated that DNA methylation plays an essential role for the maintenance of X- and Y-inactivation of the PAR2 gene SYBL1; here we report that the silencing of the second repressed PAR2 gene, SPRY3, appears to be independent of DNA methylation. In contrast to SYBL1, the inactive X and Y alleles of SPRY3 are not reactivated in cells treated with a DNA methylation inhibitor and in cells from ICF (immunodeficiency, centromeric instability, facial anomalies) syndrome patients, which have mutations in the DNA methyltransferase gene DNMT3B. SPRY3 X- and Y-inactivation is associated with a differential enrichment of repressive histone modifications and the recruitment of Polycomb 2 group proteins compared to the active X allele. Another major factor in SPRY3 repression is late replication; the inactive X and Y alleles of SPRY3 have delayed replication relative to the active X allele, even in ICF syndrome cells where the closely linked SYBL1 gene is reactivated and advanced in replication. The relatively stable maintenance of SPRY3 silencing compared with SYBL1 suggests that genes without CpG islands may be less prone to reactivation than previously thought and that genes with CpG islands require promoter methylation as an additional layer of repression.

Alleles↗

PubMed2026

Inhibition of EED enhances osteogenic differentiation and bone formation: a potential therapeutic strategy for osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a heterogeneous group of inherited connective tissue disorders primarily caused by dominant mutations in COL1A1 or COL1A2 that impair type I procollagen folding and secretion. Misfolded collagen accumulates in the endoplasmic reticulum (ER), triggering ER stress and osteoblast dysfunction, and bone fragility. Current pharmacologic therapy focuses on inhibiting bone resorption but has limited efficacy and does not address the underlying biology of the disease. The epigenetic regulator polycomb-repressive complex 2 (PRC2) has emerged as an important regulator of bone formation. Genetic and pharmacologic disruption of PRC2 enhanced osteogenic differentiation in WT cells. Here, we demonstrate that inhibition of the PRC2 through targeting its essential component embryonic ectoderm development (EED) enhances osteogenic differentiation, improves bone architecture in male Col1a2 +/G610C OI mouse models, modulates the integrated stress response (ISR), and improves ER morphology in OI cells. These findings identify EED inhibition as a novel epigenetic strategy to restore collagen homeostasis and improve skeletal integrity in OI.

ER stress↗

PubMed1991

A sequence motif found in a Drosophila heterochromatin protein is conserved in animals and plants.

Modifiers of position-effect-variegation in Drosophila encode proteins that are thought to modify chromatin, rendering it heritably changed in its expressibility. In an attempt to identify similar modifier genes in other species we have utilized a known sequence homology, termed chromo box, between a suppressor of position-effect-variegation, Heterochromatin protein 1 (HP1), and a repressor of homeotic genes, Polycomb (Pc). A PCR generated probe encompassing the HP1 chromo box was used to clone full-length murine cDNAs that contain conserved chromo box motifs. Sequence comparisons, in situ hybridization experiments, and RNA Northern blot analysis suggest that the murine and human sequences presented in this report are homologues of the Drosophila HP1 gene. Chromo box sequences can also be detected in other animal species, and in plants, predicting a strongly conserved structural role for the peptide encoded by this sequence. We propose that epigenetic (yet heritable) changes in gene expressibility, characteristic of chromosomal imprinting phenomena, can largely be explained by the action of such modifier genes. The evolutionary conservation of the chromo box motif now enables the isolation and study of putative modifier genes in those animal and plant species where chromosomal imprinting has been described.

Amino Acid Sequence↗

PubMed1995

The chromo shadow domain, a second chromo domain in heterochromatin-binding protein 1, HP1.

The chromo domain was originally identified as a protein sequence motif common to the Drosophila chromatin proteins, Polycomb (Pc) and heterochromatin protein 1 [HP1; Paro and Hogness (1991) Proc. Natl. Acad. Sci. USA, 88, 263-267; Paro (1990) Trends Genet., 6, 416-421]. Here we describe a second chromo domain-like motif in HP1. Subsequent refined searches identified further examples of this chromo domain variant which all occur in proteins that also have an N-terminally located chromo domain. Due to its relatedness to the chromo domain, and its occurrence in proteins that also have a classical chromo domain, we call the variant the 'chromo shadow domain'. Chromo domain-containing proteins can therefore be divided into two classes depending on the presence, for example in HP1, or absence, for example in Pc, of the chromo shadow domain. We have also found examples of proteins which have two classical chromo domains. The Schizosaccharomyces pombe SWI6 protein, involved in repression of the silent mating-type loci, is a member of the chromo shadow group. The similar modular architecture of SpSW16, HP1 and HP1-like proteins supports the model that the specificity of action of chromatin proteins is generated by combinations of protein modules.

Amino Acid Sequence↗

PubMed2026

EGFR-co-amplified lncRNA ELDR drives glioblastoma tumorigenicity by enhancing BMI1 activity.

BACKGROUND: In glioblastoma (GBM), epidermal growth factor receptor (EGFR) amplification, one of the most prevalent genetic alterations, often occurs on extrachromosomal DNAs (ecDNAs) that contain amplified oncogenes and regulatory elements, driving tumor progression. Despite the central oncogenic role of EGFR amplification, therapeutic strategies targeting EGFR have demonstrated limited clinical efficacy, suggesting that additional mechanisms may underlie EGFR-driven GBM malignancy and treatment resistance. Long non-coding RNAs (lncRNAs) are critical regulators in cancer; however, the roles of EGFR-associated lncRNAs-particularly those localized on ecDNA-in GBM tumorigenicity and therapeutic resistance remain poorly understood. METHODS: Transcriptomic and genomic analyses were performed to identify lncRNAs co-amplified with EGFR. Biochemical and molecular biological studies were carried out to reveal the mechanisms. In vivo xenograft models were used to evaluate the tumorigenicity and the therapeutic efficacy of combination treatment strategies. RESULTS: The lncRNA EGFR long non-coding downstream RNA (ELDR) was co-amplified with EGFR on ecDNA and chromosomes and was associated with poor prognosis in glioma. ELDR promoted GBM tumorigenicity through a BMI1-dependent epigenetic mechanism operating in parallel with canonical EGFR signaling. Mechanistically, ELDR interacted with purine-rich element-binding protein A (PURA), disrupted the inhibitory PURA-BMI1 interaction, and thereby enhanced the activity of BMI1, a core component of Polycomb repressive complex 1 (PRC1). Therapeutically, combining a BMI1 inhibitor or ELDR-targeting antisense oligonucleotides (ASOs) with an EGFR inhibitor erlotinib significantly enhanced antitumor efficacy in preclinical models of  EGFR  -amplified GBM with high ELDR expression. CONCLUSION: EGFR co-amplified ELDR promotes GBM tumorigenicity by enhancing BMI1 activity. Targeting the ELDR-BMI1 axis in combination with EGFR inhibition represents a promising therapeutic strategy for a subset of  EGFR  -amplified GBMs with high ELDR expression.

EGFR↗

PubMed2026

Combination of EZH2 and MEK inhibitors as an effective therapy for neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors.

BACKGROUND: Neurofibromatosis type 1 (NF1)-associated malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas with poor outcomes and limited therapeutic options. Although mitogen-activated protein kinase kinase (MEK) inhibitors are active in benign plexiform neurofibromas, their efficacy in MPNST treatment is modest. Enhancer of zeste homolog 2 (EZH2) inhibitors are preclinically efficacious in MPNST treatment, but their mechanisms of action remain unclear. We evaluated the therapeutic potential and molecular mechanism of combined EZH2 and MEK inhibitors in NF1-associated MPNST. METHODS: Five human NF1-associated MPNST cell lines were exposed to EZH2 and/or MEK inhibitors. Cell growth and apoptosis were quantified over time. Therapeutic efficacy was tested in a subcutaneous xenograft model. Proliferation and apoptosis in tumors were assessed using standard histologic markers, and intracellular localization of phosphorylated extracellular signal-regulated kinase (pERK) was examined using fluorescent immunohistochemistry. RESULTS: Monotherapy with EZH2 or MEK inhibitors reduced proliferation and increased apoptosis across all MPNST lines. Combination therapy produced greater tumor cell growth suppression and marked increases in apoptosis. In vivo, the combination significantly delayed tumor progression compared with monotherapy, with concomitant reductions in proliferative indices and increases in apoptotic indices. EZH2 inhibitor limited nuclear pERK entry. CONCLUSIONS: Dual EZH2 and MEK inhibitors yield additive antitumor activity in NF1-associated MPNST. Although the molecular mechanism could not be elucidated, our findings suggest that EZH2 inhibitors exhibited a polycomb repressive complex 2-independent, noncanonical mechanism characterized by pERK nuclear translocation restriction, providing a strong rationale for clinical evaluation of this combination in NF1-associated MPNST.

EZH2 inhibitor↗

PubMed2003

Isolation and expression analysis of petunia CURLY LEAF-like genes.

The Arabidopsis CURLY LEAF (CLF) gene is required to repress transcription of the class C gene AGAMOUS (AG) in whorls 1 and 2 of flowers and also in vegetative organs. CLF encodes a protein with homology to the product of the Drosophila Polycomb-group gene Enhancer of zeste [E(z)], which is involved in embyogenesis. In this study, we isolated three petunia CLF-like genes (PhCLF1, PhCLF2 and PhCLF3) based on the sequence homology between CLF and E(Z). Sequence analysis suggests that PhCLF1 and PhCLF2 are orthologs of CLF, whereas PhCLF3 is an ortholog of the Arabidopsis gene EZA1. We identified several conserved domains among products of PhCLF genes and related genes. PhCLF1 and PhCLF2 were expressed in all floral organs and leaves. The PhCLF1 transcripts were accumulated especially in corolla limbs, and contained several alternatively spliced RNA species. PhCLF1 and PhCLF2 do not appear to be the BLIND gene, which is required to repress transcription of the petunia class C gene, but their expression was affected by the homeotic conversion of organs in the blind flower. Our findings show that expression of PhCLF1 is regulated differently from that of PhCLF2, and suggest that the two petunia CLF orthologs function differently from each other.

Alternative Splicing↗

PubMed2025

Foxh1 is a locus-specific PRC2 recruiter governing germ layer silencing.

Polycomb Repressive Complex 2 (PRC2) establishes H3K27me3 marks to shape spatiotemporal gene expression during embryogenesis. While its dysregulation is linked to developmental disorders, cancer, and aging, the mechanisms guiding PRC2 to specific genomic loci remain a subject of ongoing debate. A prevailing model proposes that PRC2 recruitment occurs via its intrinsic affinity for chromatin rather than through sequence-specific transcription factors. Here, we provide evidence that the maternally deposited pioneer transcription factor Foxh1 plays a critical role in directing PRC2 to specific genomic loci during zygotic genome activation in Xenopus. Foxh1 is a critical transcription factor mediating Nodal signaling, but it also plays an earlier role by pre-binding enhancers prior to signaling activation. This pre-binding is essential for forming enhanceosome complexes that trigger mesendodermal gene expression and drive gastrulation, in cooperation with other maternal transcription factors. Using maternal Foxh1-null embryos, we demonstrate that Foxh1 directly recruits Ezh2, the catalytic subunit of PRC2, to Foxh1-bound loci. Loss of Foxh1 impairs Ezh2 recruitment, leading to a global reduction in H3K27me3. These findings support a dual-function model in which Foxh1 not only activates endodermal gene expression in endoderm, but also recruits PRC2 to silence the same genes in ectoderm. This dual activity of Foxh1 allows the spatially coordinated epigenetic states of the endodermal gene regulatory program during early embryogenesis.

CRISPR/Cas9↗

PubMed2025

Multiple Epigenetic Mechanisms Functionally Cooperate to Silence Expression of Somatostatin Receptor Type 2 in Pancreatic Neuroendocrine Tumors.

Pancreatic neuroendocrine tumors (PNETs) are a rare and understudied set of cancers, with increasing incidence. Neuroendocrine tumors are unique in the fact that they express high levels of the somatostatin receptor type 2 (SSTR2), which represents a target for both tumor imaging and therapeutics. PNET grade inversely correlates with SSTR2 tumor staining and higher tumor grade is associated with poor patient prognosis. With no known mutations, SSTR2 expression is believed to be lost through aberrant epigenetic mechanisms. Enhanced knowledge of the epigenetic biology and players controlling SSTR2 expression may allow for identification of novel PNET imaging and treatment modalities. Through in-depth studies, we found that the specific de novo DNA methyltransferase (DNMT), DNMT3B, is responsible for SSTR2 gene CpG methylation and silencing. Using DNMT3B as a starting point, along with the concept of functional crosstalk between various epigenetic mechanisms, we further discovered that Polycomb Repressor Complexes 1 and 2 (PRC1 and PRC2) play important roles in silencing SSTR2. Moreover, we found several histone lysine demethylases, enzymes that remove activating histone H3K4 methylation marks, to be critical for silencing expression of SSTR2. We additionally identified several chromatin remodeling enzymes/complexes as cellular factors that negatively regulate SSTR2 expression. Finally, using the HiBiT luminescent reporter system, we exploited functional chemo-genomic screens to further expand our knowledge of SSTR2 epigenetic control. These screens both reinforced several of our initial findings and helped to identify additional silencing mechanism potentially regulating SSTR2 expression. A commonality in our findings point to the presence, or necessity, of Class I HDACs in nearly all the epigenetic silencing mechanisms characterized. Overall, our work demonstrates that SSTR2 gene expression is likely silenced through various dynamic and interconnected epigenetic events, resulting in a compacted, transcriptionally repressed chromatin environment. Our study offers novel potential therapeutic targets and combinations to best increase expression of SSTR2, which are currently being tested in pre-clinical studies from our group, with the goal of future clinical trials aimed at increasing SSTR2 expression in high-grade, SSTR2-low NET patients.

Journal Article↗

PubMed1987

The expression and regulation of Sex combs reduced protein in Drosophila embryos.

Homeotic genes are expressed in spatially precise patterns during Drosophila development to control segmental differentiation. The Sex combs reduced (Scr) gene of the Antennapedia gene complex is involved in the determination of the labial and prothoracic segments of the embryo. To study both the wild-type pattern of Scr expression and the regulatory relationships of Scr to other regulatory genes, an antibody probe that detects the Scr protein was prepared. We find that the Scr gene product is expressed in a dynamic pattern over the course of embryogenesis, beginning in the ectoderm in parasegment 2 while the germ band is elongated and extending to parasegment 3 during the completion of germ band shortening. The locations of Scr protein correlate well with the part of the embryo that are altered in Scr- mutants. After head involution occurs, Scr protein is also expressed in the ganglion corresponding to parasegment 2 of the ventral nervous system. The precise spatial expression of Scr is attained through regulation by both homeotic genes and segmentation genes. The lack of proper Antennapedia or Polycomb gene function causes ectopic Scr protein expression. Mutations in the segmentation genes fushi tarazu, hunchback, Krüppel, and giant alter the spatial pattern of Scr expression.

Animals↗

PubMed1996

Fab-7 functions as a chromatin domain boundary to ensure proper segment specification by the Drosophila bithorax complex.

Fab-7 deletions in the bithorax complex have a novel gain-of-function phenotype, typically transforming parasegment 11 (PS11) into PS12 identity. Genetic analysis indicates that removal of the Fab-7 element results in the fusion of the iab-6 (PS11) and iab-7 (PS12) cis-regulatory domains into a single regulatory domain that inappropriately regulates Abdominal-B in PS11. This has led to the hypothesis that Fab-7 is a chromatin domain boundary that normally functions to ensure the autonomous activity of the iab-6 and iab-7 cis-regulatory domains. We use several different enhancer blocking assays to demonstrate that Fab-7 has the insulating properties expected of a domain boundary. We define a minimal fragment of Fab-7 sufficient for enhancer blocking, and demonstrate that it is completely distinct from an adjacent Polycomb-dependent silencer. We compare Fab-7 to the su(Hw) insulator element, and show that Fab-7 enhancer blocking activity is intermediate between that of five and twelve reiterated binding sites for the Su(Hw) protein. These results support the model that Fab-7 functions as a domain boundary within the context of the bithorax complex, making Fab-7 one of the first boundary elements that is known to have an essential function in vivo.

Animals↗