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Identification and Functional Validation of Novel Foxp2 Regulatory Transcription Factors in Human Cell Lines

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Identification and Functional Validation of Novel Foxp2 Regulatory Transcription Factors in Human Cell Lines IDENTIFICATION AND FUNCTIONAL VALIDATION OF NOVEL FOXP2 REGULATORY TRANSCRIPTION FACTORS IN HUMAN CELL LINES Quimbaya, Mauricio1 and España, Jina Marcela1 1Pontificia Universidad Javeriana Cali, Colombia ABSTRACT Different types of genetic analyzes based on individuals with different hereditary forms of speech disorders, such as verbal dyspraxia and some types of autism, have allowed the identification of specific genes closely associated with the disorders mentioned above. In humans, the transcription factor FOXP2 has been widely studied. Mutations in FOXP2 are directly associated with inherited verbal dyspraxia and speech disorders. However, there is little experimental evidence on which genes or transcription factors directly regulate FOXP2, from this point of view, it is essential to determine the transcriptional regulators that act upstream of FOXP2. The identification of new transcription factors associated with FOXP2 regulation will allow the construction of more holistic and inclusive networks, providing an important advance in the identification of molecular pathways involved in the establishment of neural circuit associated with the evolution of vertebrate communication skills. In the same way, the identification of specific regulatory elements that control FOXP2 expression could be of great importance for the appearance of new therapies to prevent or control nervous system development pathologies, specifically those related to speech and language. Here, four transcription factors were chose to evaluate their regulation function with FOXP2. POU3F2 and TBR1 showed great significance in the study since both confirmed a positive FOXP2 regulation and have special roles in the nervous system development. INTRODUCTION Language and communication are inherent characteristics of the human brain with great importance in the establishment of social relations. Complications during language and communication development relay on specific dysfunctions at neuronal and nervous system scales. These inabilities have not been extensively analyzed from a genetics perspective. During the 80s a case of study was followed in three generations within a single family showing verbal disorders. The genetic analysis identified a mutation in the FOXP2 gene, awakening the interest for many neuroscientists to study it thoroughly, trying to understand how only one particular gene might contribute to human communication. This approach opened a new era for language and communication understanding from a genetics perspective. Known as the communication gene, the transcription factor FOXP2 has been extensively studied in the nervous system development. FOXP2 expression is confined to specific brain regions and its expression is highly conserved in vertebrates. Numerous disruptions and alterations in this gene have been associated with deficits in human language development. Similarly, the understanding of FOXP2 control and signaling, has allowed the understanding of synaptic plasticity, the motor ability of mice and the mechanism of songbirds learning. The disorders associated with FOXP2 are due to 1) gene deletion (52% of the affected individuals), 2) specific variant sequences within the gene (~ 29%), 3) maternal uniparental disomy of chromosome 7 that reduces the expression of FOXP2 (~ 11%) and 4) structural variants of the gene (translocations and inversion) (~ 8%) [1]. One of the most common disorders associated with FOXP2 alterations is speech apraxia, characterized by disturbances in speech planning, affecting the production, pronunciation and timing of sounds, syllables and words [2]; apraxia that hinders the transformation of sounds into syllables, syllables into words and words into matching phrases, affects 10% of the population [3]. Other FOXP2 disorders include oral motor dyspraxia, which obstructs the planning of oral movements [4]; dysarthria, which interferes with the quality of the voice and affect the neuromuscular side of speech [5]; the difficulty in receiving and expressing the language (Watkins et al., 2002), deficiency in reading and writing [6]; the difficulty of developing fine motor skills [7] among others. The aim of the present research project is to propose a new genetic approach to identify and validate novel FOXP2 regulatory transcription factors. The identification of these regulatory elements will contribute to the generation of new information for the scientific community, being of high significance in the elucidation of new therapies to prevent pathologies associated with the nervous system development. THEORIC FRAME The 114076877-positional substitution in FOXP2 eighth intron, significantly affects the expression of the gene since it is located in a conserved sequence fundamental for POU3F2 binding, an important neural transcription factor [8]. The direct interaction between POU3F2 and FOXP2 is also supported by their expression pattern since both are exclusively expressed in postmitotic neurons, so it is possible to assume that FOXP2 regulation by POU3F2 occurs precisely in neuronal tissue [8]. Similarly, Bao and collaborators [9] reported, that the CTCF protein binds upstream and downstream to the FOXP2 gene, moreover, Sakai and colleagues [10] and Deriziotis teamwork [11] reported in a protein interaction study based on autism disorders, that the transcription factor TBR1 interacts physically with FOXP2. It is important to highlight the importance of TBR1 in the development of the nervous system, since it is a neuron-specific transcription factor with key roles in nervous system patterning, regulating neuronal identity in cortical development, with numerous implications in the autism disorder [12]. Morelli and colleagues [13] reported a young woman case with severe language disorders who presented a chromosomal rearrangement involving an inversion of chromosome 7 that was translocated to chromosome 11. The karyotype of the young woman, together with the clinical history that included sever complications in neurodevelopment and language abilities, indicated that the different defects were probably associated with the FOXP2 gene. The breaking point was located at 7q31 position, more specifically 200 Kb downstream to the 3'UTR of FOXP2. In this region, numerous miRNA bind, influencing not only FOXP2 expression, but also, other genes such as ROBO2, a gene associated with pathologies of the nervous system, such as autism and dyslexia [14]. Additionally, it was possible to identify and characterize a localized regulatory element 205kb downstream FOXP2, which includes an open chromatin region with specific histone modifications, typical from an enhancer region, suggesting that the 7q31 breakpoint could interfere with FOXP2 expression. The same region has been also documented as the genomic binding site of transcription factors such as PPP1R3A, MDFIC and TFEC [15]. METHODS AND RESULTS 1. Identification of novel transcription factors, involved in nervous system development that might interact with FOXP2. For the selection of FOXP2 potential interactors, different filters were applied using four bioinformatics databases: MotifMap, Uniprot, COXPRESdb and Cytoscape. From the four, two of them were relevant in the study. Table 1. Transcription factors potentially associated with FOXP2 according to MotifMap database. Name Protein name Name Protein name Name Protein name Pancreas/duodenum Forkhead box protein TBR1 T-Box, Brain 1 ipf1 FOXF2 homeobox protein 1 F2 POU domain, class Homeobox protein Cdx-2 FOXD1 Forkhead box protein D1 POU3F2 3, transcription CDX-2 factor 2 ARP- Homeobox protein Pituitary homeobox HOXB9 FOXO1 Forkhead box protein O1 1(COUP- Hox-B9 2 TF2) Hepatocyte nuclear factor Homeobox protein HOXA9 Homeobox A9 HNF3beta NKX25 3-beta Nkx-2.5 TAL BHLH Homeobox protein TAL1 Transcription Factor Freac-2 Forkhead box protein F2 NKX22 Nkx-2.2 1 Forkhead box Homeobox protein FOXM1 Freac-4 Forkhead box protein D1 Nkx3-2 protein M1 Nkx-3.2 Homeobox protein Forkhead box protein Barx1 Meis1 Homeobox protein Meis1 Freac-3 BarH-like 1 C1 vasoconstriction gliogenesis muscle organ development generation of neurons vascular smooth muscle contraction nervous system development regulation of blood vessel size smooth muscle contraction skeletal system development vascular process in circulatory neurogenesis system organ development negative regulation of locomotion vasculature development blood circulation muscle hypertrophy neuron differentiation tissue development muscle contraction system development muscle structure development muscle tissue development circulatory system processmuscle system process blood vessel development regulation of locomotion cell differentiation blood vessel remodeling anatomical structure development system process cell development multicellular organismal process angiogenesis positive regulation of locomotion neuron development blood vessel morphogenesis neuron projection morphogenesis regulation of cell migration negative regulation of biological process cellular developmental process positive regulation of biological cell projection morphogenesis anatomical structure morphogenesis process positive regulation of cell migration multicellular organismal neuron projection development regulation of biological process development negative regulation of angiogenesis cell projection organization regulation of multicellular organismal process developmental process regulation of cell morphogenesis cellular process regulation of anatomical structure regulation of developmental process morphogenesis activation
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