The Rhox gene cluster suppresses germline LINE1 transposition.

Published on Jun 8, 2021in Proceedings of the National Academy of Sciences of the United States of America9.412
· DOI :10.1073/PNAS.2024785118
Kun Tan32
Estimated H-index: 32
(UCSD: University of California, San Diego),
Matthew E Kim (UCSD: University of California, San Diego)+ 5 AuthorsMiles F. Wilkinson63
Estimated H-index: 63
(UCSD: University of California, San Diego)
Source
Abstract
Transposable elements (TEs) are mobile sequences that engender widespread mutations and thus are a major hazard that must be silenced. The most abundant active class of TEs in mammalian genomes is long interspersed element class 1 (LINE1). Here, we report that LINE1 transposition is suppressed in the male germline by transcription factors encoded by a rapidly evolving X-linked homeobox gene cluster. LINE1 transposition is repressed by many members of this RHOX transcription factor family, including those with different patterns of expression during spermatogenesis. One family member-RHOX10-suppresses LINE1 transposition during fetal development in vivo when the germline would otherwise be susceptible to LINE1 activation because of epigenetic reprogramming. We provide evidence that RHOX10 suppresses LINE transposition by inducing Piwil2, which encodes a key component in the Piwi-interacting RNA pathway that protects against TEs. The ability of RHOX transcription factors to suppress LINE1 is conserved in humans but is lost in RHOXF2 mutants from several infertile human patients, raising the possibility that loss of RHOXF2 causes human infertility by allowing uncontrolled LINE1 expression in the germline. Together, our results support a model in which the Rhox gene cluster is in an evolutionary arms race with TEs, resulting in expansion of the Rhox gene cluster to suppress TEs in different biological contexts.
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#1Young Hwang (UPenn: University of Pennsylvania)H-Index: 20
#2Shinnosuke Suzuki (UTSA: University of Texas at San Antonio)H-Index: 2
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Establishment of spermatogonia throughout the fetal and postnatal period is essential for production of spermatozoa and male fertility. Here, we establish a protocol for in vitro reconstitution of human prospermatogonial specification whereby human primordial germ cell (PGC)-like cells differentiated from human induced pluripotent stem cells are further induced into M-prospermatogonia-like cells and T1 prospermatogonia-like cells (T1LCs) using long-term cultured xenogeneic reconstituted testes. ...
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#1Bhavana Tiwari (UTSW: University of Texas Southwestern Medical Center)H-Index: 6
#2Amanda E. Jones (UTSW: University of Texas Southwestern Medical Center)H-Index: 5
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p53 is a potent tumor suppressor and commonly mutated in human cancers. Recently, we demonstrated that p53 genes act to restrict retrotransposons in germline tissues of flies and fish but whether this activity is conserved in somatic human cells is not known. Here we show that p53 constitutively restrains human LINE1s by cooperatively engaging sites in the 5'UTR and stimulating local deposition of repressive histone marks at these transposons. Consistent with this, the elimination of p53 or the ...
13 CitationsSource
#1Kun Tan (UCSD: University of California, San Diego)H-Index: 32
#2Samantha H. Jones (UCSD: University of California, San Diego)H-Index: 4
Last. Miles F. Wilkinson (UCSD: University of California, San Diego)H-Index: 63
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The UPF3B-dependent branch of the nonsense-mediated RNA decay (NMD) pathway is critical for human cognition. Here, we examined the role of UPF3B in the olfactory system. Single-cell RNA-sequencing (scRNA-seq) analysis demonstrated considerable heterogeneity of olfactory sensory neuron (OSN) cell populations in wild-type (WT) mice, and revealed that UPF3B loss influences specific subsets of these cell populations. UPF3B also regulates the expression of a large cadre of antimicrobial genes in OSNs...
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#1Kun Tan (UCSD: University of California, San Diego)H-Index: 32
#2Hye-Won Song (UCSD: University of California, San Diego)H-Index: 15
Last. Miles F. Wilkinson (UCSD: University of California, San Diego)H-Index: 63
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Spermatogonial stem cells (SSCs) are essential for the generation of sperm and have potential therapeutic value for treating male infertility, which afflicts >100 million men world-wide. While much has been learned about rodent SSCs, human SSCs remain poorly understood. Here, we molecularly characterize human SSCs and define conditions favoring their culture. To achieve this, we first identified a cell-surface protein, PLPPR3, that allowed purification of human primitive undifferentiated spermat...
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#1Pablo Tristan-Ramos (UGR: University of Granada)H-Index: 4
#2Santiago Morell (UGR: University of Granada)H-Index: 4
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The cell culture-based retrotransposition reporter assay has been (and is) an essential tool for the study of vertebrate Long INterspersed Elements (LINEs). Developed more than 20 years ago, this a...
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#1Kun Tan (UCSD: University of California, San Diego)H-Index: 32
#2Hye-Won Song (UCSD: University of California, San Diego)H-Index: 15
Last. Miles F. Wilkinson (UCSD: University of California, San Diego)H-Index: 63
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Pro-spermatogonia (SG) serve as the gateway to spermatogenesis. Using single-cell RNA sequencing (RNAseq), we studied the development of ProSG, their SG descendants, and testicular somatic cells, during the perinatal period in mice. We identified both gene and protein markers for 3 temporally distinct ProSG cell subsets, including a migratory cell population with a distinct transcriptome from the previously defined T1- and T2-ProSG stages. This intermediate (I)-ProSG subset translocates from the...
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#1Özgen Deniz (QMUL: Queen Mary University of London)H-Index: 11
#2Jennifer M. Frost (QMUL: Queen Mary University of London)H-Index: 15
Last. Miguel R. Branco (QMUL: Queen Mary University of London)H-Index: 27
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Maintenance of genome stability requires control over the expression of transposable elements (TEs), whose activity can have substantial deleterious effects on the host. Chemical modification of DNA is a commonly used strategy to achieve this, and it has long been argued that the emergence of 5-methylcytosine (5mC) in many species was driven by the requirement to silence TEs. Potential roles in TE regulation have also been suggested for other DNA modifications, such as N6-methyladenine and oxida...
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#1Abhishek Sohni (UCSD: University of California, San Diego)H-Index: 9
#2Kun Tan (UCSD: University of California, San Diego)H-Index: 32
Last. Miles F. Wilkinson (UCSD: University of California, San Diego)H-Index: 63
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Summary Spermatogenesis has been intensely studied in rodents but remains poorly understood in humans. Here, we used single-cell RNA sequencing to analyze human testes. Clustering analysis of neonatal testes reveals several cell subsets, including cell populations with characteristics of primordial germ cells (PGCs) and spermatogonial stem cells (SSCs). In adult testes, we identify four undifferentiated spermatogonia (SPG) clusters, each of which expresses specific marker genes. We identify prot...
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Abstract Testis‐expressed X‐linked genes typically evolve rapidly. Here, we report on a testis‐expressed X‐linked microRNA (miRNA) cluster that despite rapid alterations in sequence has retained its position in the Fragile‐X region of the X chromosome in placental mammals. Surprisingly, the miRNAs encoded by this cluster (Fx‐mir) have a predilection for targeting the immediately adjacent gene, Fmr1, an unexpected finding given that miRNAs usually act in trans, not in cis. Robust repression of Fm...
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Abstract Argonaute/Piwi proteins can regulate gene expression via RNA degradation and translational regulation using small RNAs as guides. They also promote the establishment of suppressive epigenetic marks on repeat sequences in diverse organisms. In mice, the nuclear Piwi protein MIWI2 and Piwi‐interacting RNAs (piRNAs) are required for DNA methylation of retrotransposon sequences and some other sequences. However, its underlying molecular mechanisms remain unclear. Here, we show that piRNA‐de...
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Cited By2
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LINE-1 (L1) is a class of autonomous mobile genetic elements that form somatic mosaicisms in various tissues of the organism. The activity of L1 retrotransposons is strictly controlled by many factors in somatic and germ cells at all stages of ontogenesis. Alteration of L1 activity was noted in a number of diseases: in neuropsychiatric and autoimmune diseases, as well as in various forms of cancer. Altered activity of L1 retrotransposons for some pathologies is associated with epigenetic changes...
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#1Kun Tan (UCSD: University of California, San Diego)H-Index: 32
#2Hye-Won Song (UCSD: University of California, San Diego)H-Index: 15
Last. Miles F. Wilkinson (UCSD: University of California, San Diego)H-Index: 63
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Summary null null Spermatogonial stem cells (SSCs) are essential for male fertility. Here, we report that mouse SSC generation is driven by a transcription factor (TF) cascade controlled by the homeobox protein, RHOX10, which acts by driving the differentiation of SSC precursors called pro-spermatogonia (ProSG). We identify genes regulated by RHOX10 in ProSG in vivo and define direct RHOX10-target genes using several approaches, including a rapid temporal induction assay: iSLAMseq. Together, the...
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