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1.
Nature ; 629(8013): 869-877, 2024 May.
Article in English | MEDLINE | ID: mdl-38693267

ABSTRACT

Airway hillocks are stratified epithelial structures of unknown function1. Hillocks persist for months and have a unique population of basal stem cells that express genes associated with barrier function and cell adhesion. Hillock basal stem cells continually replenish overlying squamous barrier cells. They exhibit dramatically higher turnover than the abundant, largely quiescent classic pseudostratified airway epithelium. Hillocks resist a remarkably broad spectrum of injuries, including toxins, infection, acid and physical injury because hillock squamous cells shield underlying hillock basal stem cells from injury. Hillock basal stem cells are capable of massive clonal expansion that is sufficient to resurface denuded airway, and eventually regenerate normal airway epithelium with each of its six component cell types. Hillock basal stem cells preferentially stratify and keratinize in the setting of retinoic acid signalling inhibition, a known cause of squamous metaplasia2,3. Here we show that mouse hillock expansion is the cause of vitamin A deficiency-induced squamous metaplasia. Finally, we identify human hillocks whose basal stem cells generate functional squamous barrier structures in culture. The existence of hillocks reframes our understanding of airway epithelial regeneration. Furthermore, we show that hillocks are one origin of 'squamous metaplasia', which is long thought to be a precursor of lung cancer.


Subject(s)
Cell Plasticity , Epithelial Cells , Regeneration , Respiratory Mucosa , Stem Cells , Animals , Female , Humans , Male , Mice , Epithelial Cells/cytology , Epithelial Cells/pathology , Metaplasia/etiology , Metaplasia/pathology , Respiratory Mucosa/cytology , Respiratory Mucosa/injuries , Respiratory Mucosa/pathology , Stem Cells/cytology , Tretinoin/metabolism , Tretinoin/pharmacology , Vitamin A/metabolism , Vitamin A/pharmacology , Lung Neoplasms/etiology , Lung Neoplasms/pathology , Mice, Inbred C57BL
2.
Cell Rep ; 42(1): 111910, 2023 01 31.
Article in English | MEDLINE | ID: mdl-36640351

ABSTRACT

DNA elements act across long genomic distances to regulate gene expression. During transvection in Drosophila, DNA elements on one allele of a gene act between chromosomes to regulate expression of the other allele. Little is known about the biological roles and developmental regulation of transvection. Here, we study the stochastic expression of spineless (ss) in photoreceptors in the fly eye to understand transvection. We determine a biological role for transvection in regulating expression of naturally occurring ss alleles. We identify DNA elements required for activating and repressing transvection. Different enhancers participate in transvection at different times during development to promote gene expression and specify cell fates. Bringing a silencer element on a heterologous chromosome into proximity with the ss locus "reconstitutes" the gene, leading to repression. Our studies show that transvection regulates gene expression via distinct DNA elements at specific timepoints in development, with implications for genome organization and architecture.


Subject(s)
Drosophila Proteins , Drosophila melanogaster , Animals , Drosophila melanogaster/genetics , Drosophila melanogaster/metabolism , Chromosomes/genetics , Chromosomes/metabolism , Gene Expression Regulation , Drosophila/metabolism , Drosophila Proteins/genetics , Drosophila Proteins/metabolism , Gene Expression
3.
Cell Rep ; 41(11): 111800, 2022 12 13.
Article in English | MEDLINE | ID: mdl-36516753

ABSTRACT

Animals sense and adapt to decreased oxygen availability, but whether and how hypoxia exposure in ancestors can elicit phenotypic consequences in normoxia-reared descendants are unclear. We show that hypoxia educes an intergenerational reduction in lipids and a transgenerational reduction in fertility in the nematode Caenorhabditis elegans. The transmission of these epigenetic phenotypes is dependent on repressive histone-modifying enzymes and the argonaute HRDE-1. Feeding naive C. elegans small RNAs extracted from hypoxia-treated worms is sufficient to induce a fertility defect. Furthermore, the endogenous small interfering RNA F44E5.4/5 is upregulated intergenerationally in response to hypoxia, and soaking naive normoxia-reared C. elegans with F44E5.4/5 double-stranded RNA (dsRNA) is sufficient to induce an intergenerational fertility defect. Finally, we demonstrate that labeled F44E5.4/5 dsRNA is itself transmitted from parents to children. Our results suggest that small RNAs respond to the environment and are sufficient to transmit non-genetic information from parents to their naive children.


Subject(s)
Caenorhabditis elegans Proteins , Caenorhabditis elegans , Animals , Caenorhabditis elegans/genetics , Caenorhabditis elegans/metabolism , Inheritance Patterns , Caenorhabditis elegans Proteins/genetics , Caenorhabditis elegans Proteins/metabolism , RNA, Small Interfering/genetics , RNA, Double-Stranded/genetics , Epigenesis, Genetic , Hypoxia/genetics , RNA Interference
4.
Dev Cell ; 51(3): 341-356.e7, 2019 11 04.
Article in English | MEDLINE | ID: mdl-31607649

ABSTRACT

Homologous chromosomes colocalize to regulate gene expression in processes including genomic imprinting, X-inactivation, and transvection. In Drosophila, homologous chromosomes pair throughout development, promoting transvection. The "button" model of pairing proposes that specific regions along chromosomes pair with high affinity. Here, we identify buttons interspersed across the fly genome that pair with their homologous sequences, even when relocated to multiple positions in the genome. A majority of transgenes that span a full topologically associating domain (TAD) function as buttons, but not all buttons contain TADs. Additionally, buttons are enriched for insulator protein clusters. Fragments of buttons do not pair, suggesting that combinations of elements within a button are required for pairing. Pairing is necessary but not sufficient for transvection. Additionally, pairing and transvection are stronger in some cell types than in others, suggesting that pairing strength regulates transvection efficiency between cell types. Thus, buttons pair homologous chromosomes to facilitate cell-type-specific interchromosomal gene regulation.


Subject(s)
Chromosome Pairing/genetics , Chromosomes/genetics , Drosophila melanogaster/genetics , Gene Expression Regulation , Genetic Loci , Animals , Chromatin/metabolism , Insulator Elements/genetics , Transgenes
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