Adaptive changes in the transcription factor HoxA-11 are essential for the evolution of pregnancy in mammals

Lynch, Vincent J.; Tanzer, Andrea; Wang, Yajun; Leung, Frederick Chi-Ching; Gellersen, Birgit; Emera, Deena; Wagner, Günter P.

doi:10.1073/pnas.0802355105

Cited by 90 publications

(100 citation statements)

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“…These changes are in addition to the well-established transcriptional rewiring events whereby the promoters of conserved genes in related species differ in the presence/absence of TF binding site(s) (1,37,38). While there are a few reports of evolutionary changes in eukaryotic TFs contributing to the modification of gene-regulatory networks (6)(7)(8)33), alterations in gene regulation and phenotypic differences in eukaryotes have been ascribed primarily to gains and/or losses of TF binding sites (3,5,10). Our results (Fig.…”

Section: Discussionmentioning

confidence: 50%

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Transcription factor function and promoter architecture govern the evolution of bacterial regulons

Pérez

Groisman

2009

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

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Evolutionary changes in ancestral regulatory circuits can bring about phenotypic differences between related organisms. Studies of regulatory circuits in eukaryotes suggest that these modifications result primarily from changes in cis-regulatory elements (as opposed to alterations in the transcription factors that act upon these sequences). It is presently unclear how the evolution of gene regulatory circuits has proceeded in bacteria, given the rampant effects of horizontal gene transfer, which has significantly altered the composition of bacterial regulons. We now demonstrate that the evolution of the regulons governed by the regulatory protein PhoP in the related human pathogens Salmonella enterica and Yersinia pestis has entailed functional changes in the PhoP protein as well as in the architecture of PhoP-dependent promoters. These changes have resulted in orthologous PhoP proteins that differ both in their ability to promote transcription and in their role as virulence regulators. We posit that these changes allow bacterial transcription factors to incorporate newly acquired genes into ancestral regulatory circuits and yet retain control of the core members of a regulon.cis-regulatory elements ͉ horizontal gene transfer ͉ PhoP ͉ Salmonella ͉ Yersinia

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Section: Discussionmentioning

confidence: 50%

“…(However, some examples in which a few amino acid substitutions seem to be responsible for functional changes have also been reported (7,33).) The Salmonella and Yersinia PhoP proteins have 2 domains: a 120-residue N-terminal domain joined by a 5-residue linker to a 98-residue C-terminal domain (34).…”

Section: Discussionmentioning

confidence: 99%

Transcription factor function and promoter architecture govern the evolution of bacterial regulons

Pérez

Groisman

2009

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

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“…The evolution of positively selected sites in Hox11 genes may be associated with the evolution of snake-specific functions accompanying the appearance of truncated ribs over the cloacal region (Fig. 4), in a similar manner to that proposed for Hoxa11 and the evolution of pregnancy in mammals 25 .…”

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confidence: 84%

Changes in Hox genes’ structure and function during the evolution of the squamate body plan

Di‐Poï

Montoya‐Burgos

Miller

et al. 2010

Nature

156

183

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Hox genes are central to the specification of structures along the anterior-posterior body axis 1,2 , and modifications in their expression have paralleled the emergence of diversity in vertebrate body plans 3,4 . Here we describe the genomic organization of Hox clusters in different reptiles and show that squamates have accumulated unusually large numbers of transposable elements at these loci 5 , reflecting extensive genomic rearrangements of coding and non-coding regulatory regions. Comparative expression analyses between two species showing different axial skeletons, the corn snake and the whiptail lizard, revealed major alterations in Hox13 and Hox10 expression features during snake somitogenesis, in line with the expansion of both caudal and thoracic regions. Variations in both protein sequences and regulatory modalities of posterior Hox genes suggest how this genetic system has dealt with its intrinsic collinear constraint to accompany the substantial morphological radiation observed in this group.In many animal species, Hox genes are clustered, and their expression domains, in both time and space, reflect their respective genomic order 1 . Although this genetic system has been used as a paradigm in the study of the evolution of body plans 6 , recent studies have highlighted an unexpected diversity in Hox gene number, genomic organization and expression patterns 7,8 . In tetrapods, these genes are classified into 13 groups of paralogy and are tightly clustered at four loci: HoxA to HoxD. A clear correspondence between particular Hox groups and defined morphological boundaries along the anteroposterior axis has been documented, either by comparing expression profiles between various vertebrates or by genetic experiments in the mouse 1,3,4,9 .Vertebrate species have highly variable number of vertebrae, ranging from fewer than ten to several hundreds 10-12 , a parameter that is probably dependent on the speed of the segmentation clock relative to axial growth, as proposed for snakes 13 . Within reptiles, squamates (that is, lizards and snakes) have a large realm of morphologies, suggesting that Hox genes were modified, either in their structure or in their regulation. Previous expression analyses in snakes showed an expansion of anterior Hox gene expression along the body axis, in parallel with body plan elongation 9 , and revealed that collinearity was fully respected 14 . However, these studies involved selected genes, in the absence of genomic information. Here we describe how structural and regulatory adaptations in this gene family may have accompanied the transition towards such a body plan and suggest that the unexpected invasion of all Squamata Hox clusters by transposons might have facilitated such adaptations.We characterized the genomic organization of posterior Hox loci in the corn snake (Pantherophis guttatus) and other reptiles, including the turtle, tuatara and several lizards, with a particular focus on repeated elements that are generally excluded from these loci in tetrapods but are abundan...

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“…1). The DNA transposon MER20, located about 30 bp upstream of MER39, is common to all placental mammals (17) (Fig. 1A).…”

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confidence: 99%

Transformation of a transposon into a derived prolactin promoter with function during human pregnancy

Emera

Wagner

2012

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

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Transposable elements (TEs) are known to provide DNA for host regulatory functions, but the mechanisms underlying the transformation of TEs into cis-regulatory elements are unclear. In humans two TEs-MER20 and MER39-contribute the enhancer/ promoter for decidual prolactin (dPRL), which is dramatically induced during pregnancy. We show that evolution of the strong human dPRL promoter was a multistep process that took millions of years. First, MER39 inserted near MER20 in the primate/rodent ancestor, and then there were two phases of activity enhancement in primates. Through the mapping of causal nucleotide substitutions, we demonstrate that strong promoter activity in apes involves epistasis between transcription factor binding sites (TFBSs) ancestral to MER39 and derived sites. We propose a mode of molecular evolution that describes the process by which MER20/MER39 was transformed into a strong promoter, called "epistatic capture." Epistatic capture is the stabilization of a TFBS that is ancestral but variable in outgroup lineages, and is fixed in the ingroup because of epistatic interactions with derived TFBSs. Finally, we note that evolution of human promoter activity coincides with the emergence of a unique reproductive character in apes, highly invasive placentation. Because prolactin communicates with immune cells during pregnancy, which regulate fetal invasion into maternal tissues, we speculate that ape dPRL promoter activity evolved in response to increased invasiveness of ape fetal tissue.cis-regulatory evolution | human evolution | human pregnancy I n the pursuit to understand mechanisms underlying the evolution of gene regulation, it has become increasingly clear that transposable elements play a critical role in regulatory evolution by providing novel genetic elements, including new introns, promoters, enhancers, and insulators (1). In addition to individual examples showing that transposable elements (TEs) are associated with host regulatory function, computational work shows that TEs intersect with many promoter regions (2) and are overrepresented in predicted regulatory regions [(3, 4); see review by Feschotte (1)]. Many questions remain unanswered. How frequently are TEs actually co-opted for regulatory function? What is the adaptive significance of these events? Are TEs used by the host genome immediately upon insertion or do they require extensive sequence evolution before acquiring a biological role? What are the molecular changes that transform a transposable element into a cisregulatory element?In this paper we address the latter two questions posed above by investigating evolution of the decidual prolactin promoter in primates. In a recent paper we showed that the prolactin gene was independently recruited into uterine expression in primates, mice, and elephants by the co-option of different transposable elements, highlighting the frequency at which TEs can be recruited and their importance in gene regulatory innovation (5). Here we trace the evolutionary history and function of transposabl...

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Adaptive changes in the transcription factor HoxA-11 are essential for the evolution of pregnancy in mammals

Cited by 90 publications

References 53 publications

Transcription factor function and promoter architecture govern the evolution of bacterial regulons

Transcription factor function and promoter architecture govern the evolution of bacterial regulons

Changes in Hox genes’ structure and function during the evolution of the squamate body plan

Transformation of a transposon into a derived prolactin promoter with function during human pregnancy

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