Abstract
The epigenetic regulation of spatiotemporal gene expression is crucial for human development. Here, we present whole-genome chromatin immunoprecipitation followed by high throughput DNA sequencing (ChIP-seq) analyses of a wide variety of histone markers in the brain, heart, and liver of early human embryos shortly after their formation. We identified 40,181 active enhancers, with a large portion showing tissue-specific and developmental stage-specific patterns, pointing to their roles in controlling the ordered spatiotemporal expression of the developmental genes in early human embryos. Moreover, using sequential ChIP-seq, we showed that all three organs have hundreds to thousands of bivalent domains that are marked by both H3K4me3 and H3K27me3, probably to keep the progenitor cells in these organs ready for immediate differentiation into diverse cell types during subsequent developmental processes. Our work illustrates the potentially critical roles of tissue-specific and developmental stage-specific epigenomes in regulating the spatiotemporal expression of developmental genes during early human embryonic development.
Highlights
The epigenetic regulation of spatiotemporal gene expression is crucial for human development
After excluding H3K27ac from the transcription start sites (TSS) regions, we identified a total of 40,181 K27acϩK4me1-positive regions in these three fetal-stage organs
These findings suggested that the genes associated with these fetal stage-specific enhancers are functionally crucial for the development and physiological function of these tissues
Summary
Informed Consent and Ethics Approval of the Study—The approval of the Reproductive Study Ethics Committee of Peking University Third Hospital (research license 2012SZ013) was obtained in this study for collection and use of the embryos from the donors. For the broad domain analysis of H3K4me, we used MACS (version 2.1.0) to call the broad peaks in the replicates using the options “-fix-bimodal -broad -f BED -g hs -n chip_output -B” [37, 38]. Identification of the Enhancers—To identify the enhancer catalog, we took advantage of the H3K27ac and H3K4me ChIP-seq peaks, which are the hallmarks of putative enhancers. Identification of the Active and Poised Enhancers and the Enhancer Transition Dynamics—The enhancer activity was defined based on the ratio of the H3K4me and H3K27ac enrichment levels, according to a previous publication [20]. Functional Enrichment and Transcription Factor-binding Motif Analysis—For the given stage- or organ-specific enhancers (or super-enhancers), the functional annotation enrichment analysis was performed using GREAT [42], which is based on the neighboring potential of targeted genes. 67.1 abnormal neural tube closure maaaafaaabbbbbbiidlsnnnnnufeoooooraenrrrrrcmmmmmteotaaaaarfholllllpyprpnmpropirrehmeisiommuotspirrbtoiiaalittlaviidallvv-esesfceeoitaraslmssgdutrttidrreamdeeaaneaaolktvkkarcepfxomfelhoiorlsolormpsmlprmoapaagthetityotioneonltrnonginyg abnormal embryonic-extraembryonic boundary morphology facaaybbccnnilaooolrrpmmcialeaaflltatrlolacnhtloeiasrmneorrvpehomloogrpyhology faaaaaebbbbbtannnnnlooooogrrrrrmmmmmroaaaaawlllll tcfavhhoooleirrsrmaeeppdgteohaurrderoatdennmavqoaetuoiisdolaroapnbdplhoromiognrlegeoenamgmtnyinomarpomhrpoohlroopglhoyoglyogy absent maxillary shelf idanebccnreroearamsseaedldonnlefaeucurtoroonrtyrnacunomsrmtbeeixttremr orerplehaosloegy aaaabbbbnnnnoooorrrrmmmmaaaallll pnaniedetuurueirrtonoanatrrylapgngrloslaamlninfdeidttrpeamhrtioyosrsenpicohrloeoltgoioygny aaaabbbbnnnnoooorrrrmmmmaaaallll vbnineaecrsuitsiersoobprtrrhamaelnonbsroompiddhiytotbelmoorngoleeyrpvmehloolropghyology aaabbbnnnooorrrmmmaaalll tnmyemauxpriolalannraiycl psrihrneegclfummrsooorprrphphoroololloigfgeyyration apaabebbnrnnsoooisrrrmmmteaaanlllcraleaadtdoeriefraanhllayggalliaclaonoligdrctleeivolxalnmsmiccoouerrlpamphrhionosleyloosnggtceyyemmorphology abnormal somatotroph morphology daebcnroeramsaeldooligligooddeennddrorocyctyetemnourmphboelrogy aabbnnoorrmmaall nmeyrevleincsohnedautchtimonorphology rdeetcinreaacsoelodbnoemrvae conduction velocity cerebral edema pericardial effusion increased heart right ventricle size adimebpcnaroeirramesdaelmdcuacasrdcrdilaeiacccmomnutusrascccletleilcitocyonntrtaracctitliitliyty addebilacntroeerdamshaeeldamrvtuelsnectflrteicvlceeonmntrtiurcalsecctlielitcyontractility adaibblanntooerrdmmhaaell amcratyrovdeciaancrtrdmiciuluemscllaeyteisrsmueormphoorplohgoylogy aainbbcnnreooarrmmseaadll hmheeuaasrrcttllevaeyfinebtrerimrcmloeropsrihpzoheloolgoygy iecnancrlraderiaagsceedhdyhpheeeararttrrot pwheyight adalibtlaentroeerddmhraeelsamprtoyoncsaerdoifahl efiabretrtomionrdpuhcoelodgsytress icnacrrdeioamseydopreasthpyonse of heart to induced stress aaaaadardiaaaaeanebbbbbenbbbbnbectnnnnncennnnlnciracerrooooomoooooureeagrrrrrrrrrrlaaimmmmmmmmmmosaessecdaaaaaaaaaaeeydllllllllllddstmhrireeiheosrrpeehmooerrersplettyyyeeinnmmiilsetttacceemhhhuuahnoloenerrrollnoggooonoovcgmllcpceccooocwlyyoyyoolrbbettepttirbeeiieoeennipugissncmusmcchtiescaseoctoolucslolnrlrulipnnpastnlehuathruenomromvntlolvobotbolgeugelyurmyrmee idhaneebccmnreroeoaralmsysetaiecdldrareemnddeembballnoioaoocdodrccpeeulllsl dcduiissltatrriribbhuuettimioonnogwwloiiddbtthihn aabbnnoorrmmaall hlipeipdahtoobmileiaorsytassyisstem physiology aaaaaabbbbbbnnnnnnoooooorrrrrrmmmmmmaaaaaallllll tccslliirvphitiregeicodrlruyloelclpleasehlvtterieyenivdrslgeoieolllilllpoeeigvvdyeelllevel aadahdiadaainnbbebeebebbccnncnpcncnnrreerrroooaoooeeeaarrrtrrraaaimmmmmmsscssseeaaaaaaseeeddlllllltdddecccbbetbarihicctiinrriillrtlgiheeccoizeorguuclolysysselsullmlyicaaaaessalceatttllseltteiietrnntt/lhiierrlendggioecodrvgeoolvtcmeerehlehclilegelllonhoeevlomzoylvveesycleeeelstmellaotsresetsiedritsolareeolsvlllieeeslevvl eevell l hESC Fetal brain Adult brain Fetal heart Adult heart Fetal liver Adult liver
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