Transcriptionally active HERV-H retrotransposons demarcate topologically associating domains in human pluripotent stem cells

Zhang, Yanxiao; Li, Ting; Preissl, Sebastian; Amaral, Maria Luisa; Grinstein, Jonathan D.; Farah, Elie N.; Destici, Eugin; Qiu, Yunjiang; Hu, Rong; Lee, Ah Young; Chee, Sora; Ma, Kaiyue; Ye, Zhen; Zhu, Quan; Huang, Hui; Fang, Rongxin; Yu, Lei; Belmonte, Juan Carlos Izpisúa; Wu, Jun; Evans, Sylvia M.; Neil, C.; Ren, Bing

doi:10.1038/s41588-019-0479-7

Cited by 284 publications

(324 citation statements)

References 92 publications

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“…This further highlights the role of retrotransposons in the gene insulation (36,37), in control of chromatin topology (61), and in genome evolution (62,63). Deletion of this sequence in the mouse does not affect pigmentation or melanin levels in the skin or the eye of two independent mouse lines (Fig 4); Tyr mRNA level in the eye and skin does not depend of the Tyr 3' insulator ( Fig 5).…”

Section: Discussionmentioning

confidence: 73%

Boundary sequences flanking the mouse tyrosinase locus ensure faithful pattern of gene expression

Seruggia

Fernández

Cantero

et al. 2020

Preprint

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Control of gene expression is dictated by cell-type specific regulatory sequences that physically organize the structure of chromatin, including promoters, enhancers and insulators. While promoters and enhancers convey cell-type specific activating signals, insulators prevent the cross-talk of regulatory elements within adjacent loci and safeguard the specificity of action of promoters and enhancers towards their targets in a tissue specific manner. Using the mouse tyrosinase (Tyr) locus as an experimental model, a gene whose mutations are associated with albinism, we described the chromatin structure in cells at two distinct transcriptional states. Guided by chromatin structure, through the use of Chromosome Conformation Capture (3C), we identified sequences at the 5' and 3' boundaries of this mammalian gene that function as enhancers and insulators.By CRISPR/Cas9-mediated chromosomal deletion, we dissected the functions of these two regulatory elements in vivo in the mouse, at the endogenous chromosomal context, and proved their role as genomic insulators, shielding the Tyr locus from the expression patterns of adjacent genes.

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Section: Discussionmentioning

confidence: 73%

Boundary sequences flanking the mouse tyrosinase locus ensure faithful pattern of gene expression

Seruggia

Fernández

Cantero

et al. 2020

Preprint

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“…The ERVL LTR promoter drives early cleavage‐stage specific genes in both mouse and human embryos, and has been associated with zygotic/embryonic genome activation . Most recently, both MERVL and HERVH elements have been implicated in 3D genome organization, where their presence can affect TAD boundaries as well as nearby gene expression . As genome‐wide mapping and analysis tools continue to improve, it is likely that many more examples of TE‐derived cis ‐regulatory elements and networks will be uncovered.…”

Section: Te Dna and The Evolution Of Cis‐regulatory Networkmentioning

confidence: 99%

What Doesn't Kill You Makes You Stronger: Transposons as Dual Players in Chromatin Regulation and Genomic Variation

2020

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Transposable elements (TEs) are sequences currently or historically mobile, and are present across all eukaryotic genomes. A growing interest in understanding the regulation and function of TEs has revealed seemingly dichotomous roles for these elements in evolution, development, and disease. On the one hand, many gene regulatory networks owe their organization to the spread of cis‐elements and DNA binding sites through TE mobilization during evolution. On the other hand, the uncontrolled activity of transposons can generate mutations and contribute to disease, including cancer, while their increased expression may also trigger immune pathways that result in inflammation or senescence. Interestingly, TEs have recently been found to have novel essential functions during mammalian development. Here, the function and regulation of TEs are discussed, with a focus on LINE1 in mammals. It is proposed that LINE1 is a beneficial endogenous dual regulator of gene expression and genomic diversity during mammalian development, and that both of these functions may be detrimental if deregulated in disease contexts.

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“…To gain insight into the transcriptional regulation of HMGXB4, we performed an integrative analysis of RNA-seq (N ~300), Hi-C, ChiP-seq/ChIP-exo/CUT&RUN of transcription factors (TFs) and histone modification data over the HMGXB4 locus in HeLa, embryonic stem cells H1_ESCs and human early embryogenesis [28][29][30][31] . As KRAB-ZNF transcriptional regulators, known to recruit the TRIM28/KAP1-mediated transcriptional repression machinery to specific gene targets in early vertebrate development 32 , we mapped ChIP-exo seq peaks of 230 KRAB-ZNF proteins 33 around the genomic locus of HMGXB4.…”

Section: Hmgxb4 Is Part Of a Regulatory Network Of Stemnessmentioning

confidence: 99%

HMGXB4 TargetsSleeping BeautyTransposition to Vertebrate Germinal Stem Cells

Devaraj

Singh

Narayanavari

et al. 2020

Preprint

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Transposons are parasitic genetic elements that frequently hijack key cellular processes of the host.HMGXB4 is a Wnt signalling-associated HMG-box protein, previously identified as a transcriptional regulating host factor of Sleeping Beauty (SB) transposition. Here, we establish that HMGXB4 is highly expressed from the zygote stage, and declines after transcriptional genome activation. Nevertheless, HMGXB4 is activated by its own promoter at 4-cell stage, responding to the parental-to-zygotic transition, marks stemness, and maintains its expression during germ cell specification. The HMGXB4 promoter is located at an active chromatin domain boundary. As a vertebrate-specific modulator of SETD1A and NuRF complexes, HMGXB4 links histone H3K4 methyltransferase-and ATPdependent nucleosome remodelling activities. The expression of HMGXB4 is regulated by the KRAB-ZNF/TRIM28 epigenetic repression machinery. A post-transcriptional modification by SUMOylation diminishes its transcriptional activator function and regulates its nucleolar trafficking. Collectively, HMGXB4 positions SB transposition into an elaborate stem cell-specific transcriptional regulatory mechanism that is active during early embryogenesis and germline development, thereby potentiating heritable transposon insertions in the germline.

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Transcriptionally active HERV-H retrotransposons demarcate topologically associating domains in human pluripotent stem cells

Cited by 284 publications

References 92 publications

Boundary sequences flanking the mouse tyrosinase locus ensure faithful pattern of gene expression

Boundary sequences flanking the mouse tyrosinase locus ensure faithful pattern of gene expression

What Doesn't Kill You Makes You Stronger: Transposons as Dual Players in Chromatin Regulation and Genomic Variation

HMGXB4 TargetsSleeping BeautyTransposition to Vertebrate Germinal Stem Cells

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