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EPIGENETICS OF SPEECH AND LANGUAGE
In songbirds, epigenetic modifications related to call are reported on early-expressed genes. These genes are
associated with the activity of the cytoskeleton (Arc) that interacts with endocytosis-related proteins and
facilitates the removal of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors from
the cell membrane. Thus, a DNA methylation in the genome region upstream of the Arc is differentially
regulated through the critical period of song development. In canaries, the gene induction of histone H3.3B
and Gadd45b is higher in robust nucleus of the arcopallidum (RA) of those birds that interpret variable
[10]
and plastic songs than in birds singing crystallized songs . In addition, microRNAs (miRs) are of special
interest, with the ability to regulate neurogenesis and thereby contributing to the organization of the brain
structures underlying speech and vocal learning. In songbirds, miRs may have activating effects that support
vocal learning and multiple miRs affect neurite growth and synaptogenesis [198] . For instance, the expression
of 5 miRs in cortical auditory regions is affected by exposure to the specific song. In this way, miR-92, -124,
and -129-5p decrease, and miR-25 and -192 increase [199] . miR-124 and miR-137 conduct cell differentiation to a
neural destination by suppressing non-neuronal transcriptions or regulate the maturation of neurons [200-202] .

As epigenetic mechanisms in Foxp2, miR-9, -132 [203] and -140-5p express in the area X of the zebra finch
and positively regulate by singing in young and adults, associated with reduced levels of Foxp2 [204] . miR-9 is
express in postmitotic cortical neuron and induces or limits axon growth. It also acts through regulating
Foxp1 to target the motor neuron specification or promotes neural differentiation by suppressing proteins
involved in neural stem cell proliferation. miR-9, as a Foxp2 /miR-9 feedback loop, indirectly affects
gene expression downstream of Foxp2 [199] . The other miRs control neural maturation [203,204] . miR-3666 is
another factor that regulates FOXP2 levels in neurodevelopment and may contribute to the pathogenesis
of neurological disorders such as schizophrenia and autism [198] . Moreover, Histone variant H3.3 and miR-
[199]
128 are involved in learned vocal communication . In FOXP2 3′ untranslated region, let-7a, miR-9, and miR-
129-5p regulate its expression [201,205] . Active neuronal enhancers were predicted by strong histone-3-lysine-4-
monomethylation (H3K4Me1) and histone-3-lysine27-acetylation (H3K27Ac) within the 3C fragments at 330
and 843 kb. The 3C fragment at -37 kb encompassed a weak neural enhancer, predicted by strong H3K4Me1 and
weak H3K27Ac. In some neuronal roadmap epigenomics samples parts of the same fragment were annotated
[202]
as active transcriptional start sites, predicted by an absence of H3K4Me1 and strong H3K9Ac . Furthermore,
amongst the 61 peaks with human-specific loss of H3K4me3 is a 700-bp sequence upstream of FOXP2
[206]
transcription start site (TSS) . In songbirds, unlike Foxp2, whose differential expression at the core of the song
depends on behavior, the Foxp1 signaling pathway regulates the singing process, with mRNA enrichment in the
[203]
surrounding tissues of area X of male birds, high-level vocal center nucleus (HVC) and RA .
Regarding epigenetic factors involved in the different speech and language disorders, in silico tests identified
as factors implicated in the development of CAS to miR-182, miR-34c-5p, miR-34a, miR-449a, miR-449b, miR-
1271, miR-96, miR-9, miR-647, miR-604, miR-214, and miR-657 [207] . The same author implicated in DLD to
miR-1207-5p, miR-188-3p, miR-1225-3p, and miR-299-3p [207] . Epigenetic mechanisms may affect the expression
of KIAA0319 in the etiology of dyslexia. For instance, miR-548c-3p, may define the development of DL [208] .
Concerning ASD, it was reported a hypermethylation at oxytocin receptor gene (OXTR) in peripheral blood,
and the temporal cortex of patients [209] . As epigenetic mechanisms of FXS, a promoter hypermethylation
[64]
induces a transcription repression . An increased methylation at site H3K9 and H3K27, which modify
[64]
transcription activation, have been reported in HD .

CONCLUSION
1. Multiple genes involved in speech and language have been reported. FOXP1, FOXP2, CMIP or GNPTAB
are genes in which associations have been replicated. However, in other genes, further studies are needed to
demonstrate their linkage. The unification of criteria, the development of endophenotypes or observational
studies of genetic variants, such as GWAS, are needed to provide more robust results.