Homologous chromosomes pair in somatic cells in Drosophila, but how this occurs is poorly understood. In this issue of Developmental Cell, Viets et al. (2019) show that proteins and chromatin structure mediate pairing and argue against a DNA sequence-based mechanism

Bateman, Jack R.

Kassis, Judith A.

English

Bowdoin College

Bowdoin College Bowdoin Digital Commons Biology Faculty Publications Faculty Scholarship and Creative Work 11-4-2019 Homolog Pairing at the Push of a Button Jack R. Bateman Bowdoin College Judith A. Kassis National Institute of Child Health and Human Development (NICHD) Follow this and additional works at: https://digitalcommons.bowdoin.edu/biology-faculty-publications Recommended Citation Bateman, Jack R. and Kassis, Judith A., "Homolog Pairing at the Push of a Button" (2019). Biology Faculty Publications. 11. https://digitalcommons.bowdoin.edu/biology-faculty-publications/11 This Article is brought to you for free and open access by the Faculty Scholarship and Creative Work at Bowdoin Digital Commons. It has been accepted for inclusion in Biology Faculty Publications by an authorized administrator of Bowdoin Digital Commons. For more information, please contact mdoyle@bowdoin.edu, a.sauer@bowdoin.edu. Homolog Pairing at the Push of a ButtonJack R. Bateman1,* and Judith A. Kassis2,*1Biology Department, Bowdoin College, Brunswick, ME 04011, USA2Eunice Kennedy ShriverNational Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA*Correspondence: jbateman@bowdoin.edu (J.R.B.), jkassis@mail.nih.gov (J.A.K.)https://doi.org/10.1016/j.devcel.2019.10.014Homologous chromosomes pair in somatic cells in Drosophila, but how this occurs is poorly understood. Inthis issue of Developmental Cell, Viets et al. (2019) show that proteins and chromatin structure mediate pair-ing and argue against a DNA sequence-based mechanism.Eukaryotic genomes are highly organizedwithin the interphase nucleus, with chro-mosomes occupying distinct territoriesand folding into predictable domains alongtheir lengths (Szabo et al., 2019). InDrosophila and other dipterans, an addi-tional layer of organization exists whereinhomologous chromosomes are intimatelypaired from end to end in most somaticcells, a property called somatic homologpairing (Joyce et al., 2016). While severalpast studies have examined and charac-terized somatic homolog pairing, themolecular mechanisms that allow homolo-gouschromosomes to identify one anotherand physically pair remain poorly under-stood. Viets et al. (2019) shed light on thisquestion by identifying and characterizing‘‘buttons’’ as discrete chromosomal seg-ments that have a high capacity for homo-log pairing.Two general models can be used toframe the problem of how homologouschromosomes identify one another. In thefirst, the DNA sequence itself could beread by an unknown mechanism—in thiscase, pairing activity would be continuousand additive, predicting that any longstretch of DNA homology would pairmore easily than a shorter region of homol-ogy. In an alternative model, pairing couldbe mediated by distinct features ofchromatin structure, such as patterns oflocal DNAconformation and/or bound pro-teins. In this discontinuous model, certaingenomic regions may have a higher ca-pacity to pair than others and could there-fore serve as molecular buttons to bringtwo chromosomes together. Early studieson somatic pairing in Drosophila embryosshowed that some regions of the genomepair earlier than others, supporting adiscontinuous model (Fung et al., 1998).To explore themechanisms driving pair-ing in Drosophila, Viets et al. (2019) de-signed an ectopic pairing strategy thatemployed large transgenes encodingduplicate genomic segments insertedat an ectopic genomic location. If thegenomic segment carried by a transgenehas thecapacity tomediatesomatichomo-logpairing, itmaypairwith theendogenouslocus that shareshomologywith that trans-gene,which canbedetected viaDNA-fluo-rescence in situ hybridization (DNA-FISH)and three-dimensional imaging. Alterna-tively, transgenes that are not able tomediate pairing would not pair with theirendogenous counterparts. The authorstested dozens of different transgenes inthis assay and found that some transgeneshave the capacity to pair with their endog-enous counterparts, whereas other trans-genesdonot.Notably, all of the transgeneswere of similar size, with no significant dif-ference in transgene length between thosethat paired with their endogenous locationand those that did not. Thus, the data sup-port that the capacity to pair in this assay isconfined to discrete genomic segments,consistent with a buttonmodel for somatichomolog pairing.What, then, differentiates transgenesthat drive pairing from those that do sopoorly or not at all? Viets et al. comparedgenomic featuresof transgenes from thesetwo categories and found significant differ-ences in binding of specific insulator pro-teins and their associated co-factors (Mat-zat and Lei, 2014). Moreover, they alsofound that the two categories of transgenediffer significantly in their total clusters ofunique insulator binding sites, with pairingtransgenes having more clusters, leadingthe authors to propose a potential ‘‘insu-lator code’’ that could be a component ofa unique address for each homologousbutton. Perhaps just as interesting is thelist of genomic features that did not differsignificantly betweenpairing and non-pair-ing transgenes, including transcriptionalactivity, Polycomb group binding sites,and patterns of histone modifications.In addition to assessing bound proteins,Viets et al. analyzed DNA topology in theirpairing and non-pairing transgenic se-quences. Surprisingly, they found thatpairing transgenes were more likely toencompass regions of chromatin foldingcommonly referred to as topologicallyassociated domains (TADs), a majorcomponent of three-dimensional genomearchitecture (Szabo et al., 2019). The au-thors further explored a potential role forTAD structure by comparing the pairingcapacity of several transgenes derivedfrom overlapping genomic segments andfound that only the transgene with a com-plete TAD could drive ectopic pairing.However, not all transgenes that pairedencompassed an entire TAD, and sometransgenes with complete TADs did notpromote ectopic pairing, suggesting thatTAD structures could facilitate pairing butmay not be entirely instructive.Finally, the authors assessed a role forpairing in influencing gene expression.Classical studies have established thatwhen chromosomes are paired, regulatoryDNA present on one chromosome can actin trans on the homologous chromosome,a phenomenon known as transvection(Lewis, 1954). Viets et al. employed theirectopic pairing assay in a classic neces-sary/sufficient analysis of the spinelessgene and showed that, while pairing wasessential for transvection to occur, not allpairing transgenes supported transvec-tion, demonstrating that close proximity isnot sufficient for regulatory regions to actin trans. Interestingly, the presence of asingle insulator site could confer the abilityto support transvection to a paired trans-gene, further implicating insulators asimportant regulators of trans-interactions,Developmental CellPreviewsDevelopmental Cell 51, November 4, 2019 ª 2019 Elsevier Inc. 295in agreementwith other recent reports (Limet al., 2018; Piwko et al., 2019).The work by Viets et al. demonstrates aremarkable ability of large transgenes tofind their homologous regions on differentchromosomes, seemingly defying thechromosome territory structure of thenucleus as they do so. Prior analyses ofchromosome territories have been largelyconfined to fixed cells, presenting a staticpicture of the general positions of entirechromosomes—the study by Viets et al.may indicate that territories are more fluidthan they seem and that mixing betweenterritories is not unusual. Analyses ofchromosome positions in living cells mayhelp to shed further light on the potentialdynamic nature of interphase chromo-some biology. Furthermore, Viets et al.demonstrate a cell-type specificity to theirectopic pairing assay, suggesting thatpairing can be dramatically influenced bythe protein components and/or cell-cyclestate of a tissue. Exploration of buttonactivity in varying cell types could helpelucidate crucial differences betweencells that support ectopic pairing versusthose that do not, perhaps helping us tobetter understand why somatic homologpairing is common in dipterans but rarein other species.Somatic homolog pairing was firstdescribed over a century ago (Stevens,1908), and yet this amazing puzzle stilldefiantly resists a precisemolecular expla-nation. The work by Viets et al. (2019)strongly implicates features such as insu-lators and TADs as key components of apairing mechanism, providing clues to aidin solving this long-standing question.REFERENCESFung, J.C., Marshall, W.F., Dernburg, A., Agard,D.A., and Sedat, J.W. (1998). Homologous chro-mosome pairing in Drosophila melanogaster pro-ceeds through multiple independent initiations.J. Cell Biol. 141, 5–20.Joyce, E.F., Erceg, J., and Wu, C.T. (2016). Pairingand anti-pairing: a balancing act in the diploidgenome. Curr. Opin. Genet. Dev. 37, 119–128.Lewis, E.B. (1954). The theory and application ofa new method of detecting chromosomal rear-rangements in Drosophila melanogaster. Am.Nat. 88, 225.Lim, B., Heist, T., Levine, M., and Fukaya, T. (2018).Visualization of transvection in living Drosophilaembryos. Mol. Cell 70, 287–296.Matzat, L.H., and Lei, E.P. (2014). Surviving anidentity crisis: a revised view of chromatin insula-tors in the genomics era. Biochim. Biophys. Acta1839, 203–214.Piwko, P., Vitsaki, I., Livadaras, I., and Delidakis, C.(2019). The role of insulators in transgene transvec-tion in Drosophila. Genetics 212, 489–508.Stevens, N.M. (1908). A study of the germ cells ofcertain diptera, with reference to the heterochro-mosomes and the phenomena of synapsis.J. Exp. Zool. 5, 359–374.Szabo, Q., Bantignies, F., and Cavalli, G. (2019).Principles of genome folding into topologicallyassociating domains. Sci. Adv. 5, eaaw1668.Viets, K., Sauria, M.E.G., Chernoff, C., RodriguezViales, R., Echterling, M., Anderson, C., Tran, S.,Dove, A., Goyal, R., Voortman, L., et al. (2019).Characterization of button loci that promote ho-mologous chromosome pairing and cell-type-specific interchromosomal gene regulation. Dev.Cell 51, this issue, 341–356.Lifting Each Other Up: EpidermalStem Cells in Tissue HomeostasisValerie Horsley1,*1Department of Molecular, Cellular, and Developmental Biology and Department of Dermatology, Yale University, 219 Prospect Street,New Haven, CT 06520, USA*Correspondence: valerie.horsley@yale.eduhttps://doi.org/10.1016/j.devcel.2019.10.013Multiple stem cells maintain and repair tissues, yet how they communicate is not well understood. In thisissue of Developmental Cell, Veniaminova et al. (2019) report that each sebaceous gland is maintained bylocal stem cells and that Notch signaling regulatesmultiple aspects of their function, revealing tissue homeo-stasis mechanisms.Stem cells are essential for tissue homeo-stasis and repair after injury. The epidermisprovides an excellent model to understandstemcell regulationsincemultiple indepen-dent stemcell populations havebeen iden-tified and shown to maintain the interfollic-ular epidermis, the outermost layer of theskin, and epidermal appendages, such asthe hair follicle and the sebaceous gland(SG), the oil producing gland of the skin(Goldstein and Horsley, 2012). While it isclear that distinct stem cell populations inthe epidermis can communicate and sup-ply cells to replenish each other in extremecrisis events like tissue injury (Levy et al.,2007), the mechanisms by which this oc-curs during tissue homeostasis and withage are not well understood.In the past several years, several groupshave identified stem cells that can supportthe SG, which reside within the gland(Feldman et al., 2019; Horsley et al.,2006), in the upper hair follicle region (Jen-sen et al., 2009), and in the bulge region ofthe hair follicle (Frances and Niemann,2012), which has generated confusion inthe field regarding the source of stem cellsfor the SG (Kretzschmar et al., 2014). Inter-estingly,manymutantmice that impactSGhomeostasis (for example, see Karniket al., 2009) also possess defects in theepidermis and hair follicles, suggestingthatSGstemcellsmaysupport theseotherDevelopmental CellPreviews296 Developmental Cell 51, November 4, 2019 ª 2019 Elsevier Inc.

Homolog Pairing at the Push of a Button

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Homolog Pairing at the Push of a Button

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