A family of transposable elements co-opted into developmental enhancers in the mouse neocortex

Notwell, James H.; Chung, Tisha; Heavner, Whitney E.; Bejerano, Gill

doi:10.1038/ncomms7644

Cited by 93 publications

(84 citation statements)

References 42 publications

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“…It was recently shown that transposable elements can acquire a regulatory potential during evolution, and thus have an impact on gene expression (e.g., refs. [70][71][72]. On the other hand, vertebrate Hox clusters are largely devoid of transposable elements, unlike their flanking regulatory regions.…”

Section: Discussionmentioning

confidence: 99%

Control of Hoxd gene transcription in the mammary bud by hijacking a preexisting regulatory landscape

Schep

Necşulea

Rodríguez-Carballo

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Vertebrate Hox genes encode transcription factors operating during the development of multiple organs and structures. However, the evolutionary mechanism underlying this remarkable pleiotropy remains to be fully understood. Here, we show that Hoxd8 and Hoxd9, two genes of the HoxD complex, are transcribed during mammary bud (MB) development. However, unlike in other developmental contexts, their coexpression does not rely on the same regulatory mechanism. Hoxd8 is regulated by the combined activity of closely located sequences and the most distant telomeric gene desert. On the other hand, Hoxd9 is controlled by an enhancer-rich region that is also located within the telomeric gene desert but has no impact on Hoxd8 transcription, thus constituting an exception to the global regulatory logic systematically observed at this locus. The latter DNA region is also involved in Hoxd gene regulation in other contexts and strongly interacts with Hoxd9 in all tissues analyzed thus far, indicating that its regulatory activity was already operational before the appearance of mammary glands. Within this DNA region and neighboring a strong limb enhancer, we identified a short sequence conserved in therian mammals and capable of enhancer activity in the MBs. We propose that Hoxd gene regulation in embryonic MBs evolved by hijacking a preexisting regulatory landscape that was already at work before the emergence of mammals in structures such as the limbs or the intestinal tract.enhancers | TAD | mammalian development | mammary gland

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Section: Discussionmentioning

confidence: 99%

Control of Hoxd gene transcription in the mammary bud by hijacking a preexisting regulatory landscape

Schep

Necşulea

Rodríguez-Carballo

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Although tens of thousands of TEs in the human genome contain sequences that have evolved under purifying selection 59 , as well as sequence motifs and biochemical signatures that are consistent with some form of cis -regulatory activity 63,64 , it is important to emphasize that, thus far, very few of these elements have been characterized using functional assays. Interestingly, a recent study 65 identified a DNA segment that is highly conserved across eutherian mammals and derived from three distinct juxtaposed TEs (AmnSINE1, X6b_DNA, and MER117) that appears to function as an enhancer driving frontonasal expression of the crucial development gene Wnt5 in the mouse embryo.…”

Section: The Biological Impact Of Te Regulatory Activitiesmentioning

confidence: 99%

Regulatory activities of transposable elements: from conflicts to benefits

2016

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Transposable elements (TEs) are a prolific source of tightly regulated, biochemically active non-coding elements, such as transcription factor binding sites and non-coding RNAs. A wealth of recent studies reinvigorates the idea that these elements are pervasively co-opted for the regulation of host genes. We argue that the inherent genetic properties of TEs and conflicting relationships with their hosts facilitate their recruitment for regulatory functions in diverse genomes. We review recent findings supporting the long-standing hypothesis that the waves of TE invasions endured by organisms for eons have catalyzed the evolution of gene regulatory networks. We also discuss the challenges of dissecting and interpreting the phenotypic impact of regulatory activities encoded by TEs in health and disease.

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“…This would potentially identify specific repeats contributing to the evolution of novel neocortical enhancers in particular rather than new sequences in general. Other methods used to detect repeat enrichment (12,14,51,52) were not suitable to use here, as these methods do not consider the nonrandom variation in the ages of background sequences in the genome when estimating the background expectation for enrichment tests. First, we estimated the phylogenetic ages of individual repeats in the human genome.…”

Section: Methodsmentioning

confidence: 99%

Origin and evolution of developmental enhancers in the mammalian neocortex

Emera

Yin

Reilly

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Morphological innovations such as the mammalian neocortex may involve the evolution of novel regulatory sequences. However, de novo birth of regulatory elements active during morphogenesis has not been extensively studied in mammals. Here, we use H3K27ac-defined regulatory elements active during human and mouse corticogenesis to identify enhancers that were likely active in the ancient mammalian forebrain. We infer the phylogenetic origins of these enhancers and find that ∼20% arose in the mammalian stem lineage, coincident with the emergence of the neocortex. Implementing a permutation strategy that controls for the nonrandom variation in the ages of background genomic sequences, we find that mammal-specific enhancers are overrepresented near genes involved in cell migration, cell signaling, and axon guidance. Mammal-specific enhancers are also overrepresented in modules of coexpressed genes in the cortex that are associated with these pathways, notably ephrin and semaphorin signaling. Our results also provide insight into the mechanisms of regulatory innovation in mammals. We find that most neocortical enhancers did not originate by en bloc exaptation of transposons. Young neocortical enhancers exhibit smaller H3K27ac footprints and weaker evolutionary constraint in eutherian mammals than older neocortical enhancers. Based on these observations, we present a model of the enhancer life cycle in which neocortical enhancers initially emerge from genomic background as short, weakly constrained "proto-enhancers." Many proto-enhancers are likely lost, but some may serve as nucleation points for complex enhancers to evolve.regulatory innovation | neocortical development | epigenetics | brain evolution T he evolution of animal morphology requires changes in fundamental developmental processes. Recent studies suggest that altered gene regulation during development contributes to morphological differences between species (1-4). In several cases, individual regulatory changes have been shown to have strong effects on morphology, including reduction or loss of existing anatomical units (5-7). However, the mechanisms underlying morphological innovation, which includes the emergence of entirely novel anatomical structures and radical transformations of existing structures, remain unclear (see ref. 8).One hypothesis is that morphological innovations are driven by the widespread emergence of new regulatory functions. These may arise through several potential mechanisms: modification of regulatory elements with ancestral functions, exaptation of specific classes of transposons to generate new regulatory sequences, and emergence of new regulatory elements in situ from nonfunctional, unconstrained genomic sequences. Although recent theoretical work in flies suggests that entire regulatory elements can evolve from genomic background on relatively short time scales (9), the de novo generation of regulatory elements by transposon exaptation is a particularly compelling mechanism. Many transposons include binding sites for multiple ...

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A family of transposable elements co-opted into developmental enhancers in the mouse neocortex

Cited by 93 publications

References 42 publications

Control of Hoxd gene transcription in the mammary bud by hijacking a preexisting regulatory landscape

Control of Hoxd gene transcription in the mammary bud by hijacking a preexisting regulatory landscape

Regulatory activities of transposable elements: from conflicts to benefits

Origin and evolution of developmental enhancers in the mammalian neocortex

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