Systematic evaluation of retroviral LTRs as cis-regulatory elements in mouse embryos

Yang, Jian; Cook, Lauryn; Chen, Zhiyuan

doi:10.1016/j.celrep.2024.113775

Cited by 8 publications

(2 citation statements)

References 60 publications

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“…We found that six sgRNAs would target at most ~49% of intact LTR10 copies (356 of 734) or ~43% of predicted LTR10 enhancers and promoters (39 of 91) (table S21). This is a substantially lower proportion of elements than are usually targeted by multiplexed epigenome editing ( 52 ). It would likely be more effective to target specific LTR10 enhancers that contribute to tumor phenotypes or target the transcriptional activators of LTR10 elements instead (e.g., FOSL1 ).…”

Section: Resultsmentioning

confidence: 99%

Endogenous retroviruses mediate transcriptional rewiring in response to oncogenic signaling in colorectal cancer

Ivancevic,

Simpson,

Joyner

et al. 2024

Sci. Adv.

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Cancer cells exhibit rewired transcriptional regulatory networks that promote tumor growth and survival. However, the mechanisms underlying the formation of these pathological networks remain poorly understood. Through a pan-cancer epigenomic analysis, we found that primate-specific endogenous retroviruses (ERVs) are a rich source of enhancers displaying cancer-specific activity. In colorectal cancer and other epithelial tumors, oncogenic MAPK/AP1 signaling drives the activation of enhancers derived from the primate-specific ERV family LTR10. Functional studies in colorectal cancer cells revealed that LTR10 elements regulate tumor-specific expression of multiple genes associated with tumorigenesis, such as ATG12 and XRCC4 . Within the human population, individual LTR10 elements exhibit germline and somatic structural variation resulting from a highly mutable internal tandem repeat region, which affects AP1 binding activity. Our findings reveal that ERV-derived enhancers contribute to transcriptional dysregulation in response to oncogenic signaling and shape the evolution of cancer-specific regulatory networks.

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Section: Resultsmentioning

confidence: 99%

Endogenous retroviruses mediate transcriptional rewiring in response to oncogenic signaling in colorectal cancer

Ivancevic,

Simpson,

Joyner

et al. 2024

Sci. Adv.

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“…The MERVL LTR seems to have been co-opted by the host genome as an alternative promoter, driving the expression of genes related to the two-cell stage during ZGA [ 73 ]. Using CRISPRi (CRISPR interference), Yang et al perturbed 2,485 (93%) MERVL-LTRs (MT2-Mm) insertions in two-cell embryos, and then observed downregulation of hundreds of ZGA genes [ 78 ]. Importantly, analysis with a conservative approach of unique reads indicated that Dux directly interacted with at least 53% of all MERVL-LTRs (MT2-Mm) and at least 37% of regions that showed increased ATAC sensitivity in 2C-like cells in mESCs.…”

Section: The Role Of Nr5a2 In Zgamentioning

confidence: 99%

Pioneer Transcription Factors: The First Domino in Zygotic Genome Activation

Fu,

Ma,

Liu

2024

Biomolecules

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Zygotic genome activation (ZGA) is a pivotal event in mammalian embryogenesis, marking the transition from maternal to zygotic control of development. During the ZGA process that is characterized by the intricate cascade of gene expression, who tipped the first domino in a meticulously arranged sequence is a subject of paramount interest. Recently, Dux, Obox and Nr5a2 were identified as pioneer transcription factors that reside at the top of transcriptional hierarchy. Through co-option of retrotransposon elements as hubs for transcriptional activation, these pioneer transcription factors rewire the gene regulatory network, thus initiating ZGA. In this review, we provide a snapshot of the mechanisms underlying the functions of these pioneer transcription factors. We propose that ZGA is the starting point where the embryo’s own genome begins to influence development trajectory, therefore in-depth dissecting the functions of pioneer transcription factors during ZGA will form a cornerstone of our understanding for early embryonic development, which will pave the way for advancing our grasp of mammalian developmental biology and optimizing in vitro production (IVP) techniques.

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