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Transcriptional Interference Regulates the Evolutionary Development of Speech

ABSTRACT: The human capacity to speak is fundamental to our advanced intellectual, technological and social development. Yet so very little is known regarding the evolutionary genetics of speech or its relationship with the broader aspects of evolutionary development in primates. In this study, we describe a large family with evolutionary retrograde development of the larynx and wrist. The family presented with severe speech impairment and incremental retrograde elongations of the pisiform in the wrist that limited wrist rotation from 180° to 90° as in primitive primates. To our surprise, we found that a previously unknown primate-specific gene TOSPEAK had been disrupted in the family. TOSPEAK emerged de novo in an ancestor of extant primates across a 540 kb region of the genome with a pre-existing highly conserved long-range laryngeal enhancer for a neighbouring bone morphogenetic protein gene GDF6. We used transgenic mouse modelling to identify two additional GDF6 long-range enhancers within TOSPEAK that regulate GDF6 expression in the wrist. Disruption of TOSPEAK in the affected family blocked the transcription of TOSPEAK across the 3 GDF6 enhancers in association with a reduction in GDF6 expression and retrograde development of the larynx and wrist. Furthermore, we describe how TOSPEAK developed a human-specific promoter through the expansion of a penta-nucleotide direct repeat that first emerged de novo in the promoter of TOSPEAK in gibbon. This repeat subsequently expanded incrementally in higher hominids to form an overlapping series of Sp1/KLF transcription factor consensus binding sites in human that correlated with incremental increases in the promoter strength of TOSPEAK with human having the strongest promoter. Our research indicates a dual evolutionary role for the incremental increases in TOSPEAK transcriptional interference of GDF6 enhancers in the incremental evolutionary development of the wrist and larynx in hominids and the human capacity to speak and their retrogression with the reduction of TOSPEAK transcription in the affected family.

SUBMITTER: Mortlock D

PROVIDER: S-EPMC9323761 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Exogenous siRNAs are commonly used to regulate endogenous gene expression levels for gene function analysis, genotype-phenotype association studies and for gene therapy. Exogenous siRNAs can target mRNAs within the cytosol as well as nascent RNA transcripts within the nucleus, thus complicating siRNA targeting specificity. To highlight challenges in achieving siRNA target specificity, we targeted an overlapping gene set that we found associated with a familial form of multiple synostosis syndrome type 4 (SYSN4). In the affected family, we found that a previously unknown non-coding gene TOSPEAK/C8orf37AS1 was disrupted and the adjacent gene GDF6 was downregulated. Moreover, a conserved long-range enhancer for GDF6 was found located within TOSPEAK which in turn overlapped another gene which we named SMALLTALK/C8orf37. In fibroblast cell lines, SMALLTALK is transcribed at much higher levels in the opposite (convergent) direction to TOSPEAK. siRNA targeting of SMALLTALK resulted in post transcriptional gene silencing (PTGS/RNAi) of SMALLTALK that peaked at 72 h together with a rapid early increase in the level of both TOSPEAK and GDF6 that peaked and waned after 24 h. These findings indicated the following sequence of events: Firstly, the siRNA designed to target SMALLTALK mRNA for RNAi in the cytosol had also caused an early and transient transcriptional interference of SMALLTALK in the nucleus; Secondly, the resulting interference of SMALLTALK transcription increased the transcription of TOSPEAK; Thirdly, the increased transcription of TOSPEAK increased the transcription of GDF6. These findings have implications for the design and application of RNA and DNA targeting technologies including siRNA and CRISPR. For example, we used siRNA targeting of SMALLTALK to successfully restore GDF6 levels in the gene therapy of SYNS4 family fibroblasts in culture. To confidently apply gene targeting technologies, it is important to first determine the transcriptional interference effects of the targeting reagent and the targeted gene.

Project description:RanBPM is a ubiquitous protein that has been reported to regulate several cellular processes through interactions with various proteins. However, it is not known whether RanBPM may regulate gene expression patterns. As it has been shown that RanBPM interacts with a number of transcription factors, we hypothesized that it may have wide ranging effects on gene expression that may explain its function. To test this hypothesis, we generated stable RanBPM shRNA cell lines to analyze the effect of RanBPM on global gene expression. Microarray analyses were conducted comparing the gene expression profile of Hela and HCT116 RanBPM shRNA cells versus control shRNA cells. We identified 167 annotated genes significantly up- or down-regulated in the two cell lines. Analysis of the gene set revealed that down-regulation of RanBPM led to gene expression changes that affect regulation of cell, tissue, and organ development and morphology, as well as biological processes implicated in tumorigenesis. Analysis of Transcription Factor Binding Sites (TFBS) present in the gene set identified several significantly over-represented transcription factors of the Forkhead, HMG, and Homeodomain families of transcription factors, which have previously been demonstrated as having important roles in development and tumorigenesis. In addition, the combined results of these analyses suggested that several signaling pathways were affected by RanBPM down-regulation, including ERK1/2, Wnt, Notch, and PI3K/Akt pathways. Lastly, analysis of selected target genes by quantitative RT-qPCR confirmed the changes revealed by microarray. Several of the genes up-regulated in RanBPM shRNA cells encode proteins with known oncogenic functions, such as the RON tyrosine kinase, the adhesion molecule L1CAM, and transcription factor ELF3/ESE-1, suggesting that RanBPM functions as a tumor suppressor to prevent deregulated expression of these genes. Altogether, these results suggest that RanBPM does indeed function to regulate many genomic events that regulate embryonic, tissue, and cellular development as well as those involved in cancer development and progression.

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Transcriptional Interference Regulates the Evolutionary Development of Speech

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