Chromatin architecture has been implicated in cell-type-specific gene regulatory programs; yet, how chromatin remodels during development remains to be fully elucidated. Here, by interrogating chromatin reorganization during human pluripotent stem cell (PSC) differentiation, we discover a role for the primate-specific endogenous retrotransposon HERV-H in creating topologically associating domains (TAD) in human PSCs. Deleting these HERV-H elements eliminates their corresponding TAD boundaries and reduces transcription of upstream genes, while de novo insertion of HERV-Hs can introduce new TAD boundaries. HERV-H’s ability to create these TAD boundaries depends on high transcription, as transcriptional repression of HERV-H elements prevents formation of these boundaries. This ability is not limited to human PSCs, as these actively transcribed HERV-Hs and their corresponding TAD boundaries also appear in PSCs from other hominids but not in more distantly related species lacking HERV-Hs. Overall, our results provide direct evidence for retrotransposons in actively shaping cell-type- and species-specific chromatin architecture.

29Restructuring of chromatin architecture is an essential process for establishing cell type-30 specific gene regulatory programs in eukaryotic cells including cardiomyocytes 1-3 . 31 Supporting its importance, recent studies have reported that a substantial number of 32 mutations discovered in congenital heart disease (CHD) patients reside in genes 33 encoding chromatin remodeling factors 4-6 ; yet, how chromatin structure reorganizes to 34 assemble gene regulatory networks crucial for controlling human cardiomyocyte 35 development remains to be elucidated. Here, through comprehensively analyzing high- 36 resolution genomic maps that detail the dynamic changes of chromatin architecture, 37 chromatin accessibility and modifications, and gene expression during human 38 pluripotent stem cell (PSC) cardiomyocyte differentiation, we reveal novel molecular 39 insights into how human PSC chromatin architecture is iteratively remodeled to build 40 gene regulatory networks directing cardiac lineage specification. Specifically, we 41 uncover a new class of human PSC-specific topologically associating domain (TAD) 42 that is created by the active transcription of the primate-specific endogenous 43 retrotransposon HERV-H. Silencing of specific HERV-Hs during the initial stages of 44 human PSC differentiation or by genome-editing results in the elimination of 45 corresponding TAD boundaries and reduced transcription of genes upstream of HERV-46Hs. Supporting their role in maintaining pluripotency, we discovered that deletion of 47 specific HERV-Hs leads to more efficient human PSC cardiomyocyte differentiation. 48Using chromatin interaction maps from these analyses, we also assigned potential 49 target genes to distal regulatory elements involved in cardiac differentiation. Genome-50 editing of enhancers harboring cardiac-disease risk loci associated with congenital and 51 adult heart diseases further confirmed that these loci regulate predicted target genes. 52 Our results highlight a novel role for HERV-Hs in establishing human-specific PSC 53 chromatin architecture, delineate the dynamic gene regulatory networks during 54 cardiomyocyte development and inform how non-coding genetic variants contribute to 55 congenital and adult heart diseases.56 3 MAIN TEXT 57 The three-dimensional organization of chromosomes enables long-range 58 communications between enhancers and promoters that are critical for building complex 59 gene regulatory networks in multicellular species 1,3 . In somatic cells, interphase 60 chromosomes occupy separate nuclear spaces known as chromosome territories 7 . 61 Each chromosome is folded into a dynamic but non-random hierarchical structure 62 characterized by stretches of transcriptionally active, megabase-long compartments that 63 are interspersed with stretches of transcriptionally inactive compartments 8 . These 64 compartments can be further partitioned into topologically associating domains (TADs), 65 which exhibit high levels of intra-domain interactions and relatively low levels of inter...

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The key in vivo metabolites of a drug play an important role in its efficacy and toxicity. However, due to the low content and instability of these metabolites, they are hard to obtain through in vivo methods. Electrochemical reactions can be an efficient alternative to biotransformation in vivo for the preparation of metabolites. Accordingly, in this study, the metabolism of Z-ligustilide was investigated in vitro by electrochemistry coupled online to mass spectrometry. This work showed that five oxidation products of the electrochemical reaction were detected and that two of the oxidation products (senkyunolide I and senkyunolide H) were identified from liver microsomal incubation as well. Furthermore, after intragastric administration of Z-ligustilide in rats, senkyunolide I and senkyunolide H were detected in the rat plasma and liver, while 6,7-epoxyligustilide, a key intermediate metabolite of Z-ligustilide, was difficult to detect in vivo. By contrast, 6,7-epoxyligustilide was obtained from the electrochemical reaction. In addition, for the first time, 6 mg of 6,7-epoxyligustilide was prepared from 120 mg of Z-ligustilide. Therefore, electrochemical reactions represent an efficient laboratory method for preparing key drug metabolites.

Photocatalytic reduction of CO2 into valuable chemicals or fuels is one of the promising solutions to mitigate climate changes. However, sound photocatalysts with sensitive responses to light, efficient enrichment and...