New hope for autism with epigenetic and stem cell research

Despite the road ahead, genomics will produce results in a few years that will modify our current clinical concept of ASD.

 Joaquín Díaz Atienza

Epigenetics and autism

All cells in our body possess the same genetic makeup; however, not all genes are expressed in the same way in all cells. This is precisely because epigenetic factorsThese are instructions that tell the genome how to express itself in each part of the cell.

Among the best-known epigenetic factors is the methylation which consists of the coupling of a methyl group to amino acid cytosineThese are signs that in most cases are related to the suppression of the expression of certain genes. Other epigenetic factors are el RNA interference and chromatin.

Chromatin It is a flexible nuclear structure on which some epigenetic factors can produce modifications in the transcription of genetic information, facilitating or interrupting the information of some genes.

Direct changes can also occur in genes, either in their structure or in different DNA sequences. These are non-permanent changes, although potentially heritable, which They modify gene expression through conformational changes in the genome, without altering the sequence of nucleotides.

In short, we could say that epigenetic factors are lthe interface that puts the genome in contact with the environmental factors, there are some substances, even strong psychological experienceswhich can modify epigenetics. These changes would occur through modifications in histones during DNA methylation processes.

Regarding autism, Both the high concordance in monozygotic twins (90%) and the concordance in heterozygous siblings (<50%), as well as the presentation of autistic symptoms in other chromosomal abnormalities, would confirm the existence of specific epigenetic and environmental factors that facilitate the phenotypic expression of ASD.

In other words, epigenetic mechanisms are directly involved in both cell proliferation and differentiation, as well as in tissue specification.

Epigenetic fluctuations This is partly due to to environmental factors that would affect the phenotype through the modulation of gene expression.

Precisely the genetic modulation This could explain the complex neurobiology that leads to ASD. In humans, it has been shown that child abuse It alters DNA methylation patterns through changes in gene expression, such as the dysregulation of Growth Factors: Stimulating Hair Growth involved in neuronal development, differentiation, proliferation, and survival during development.

Both epigenetic processes, such as environmental interaction could explain the different patterns of gene expression in ASD:

• Toxins especially in parents.
• Exposure to chemicals
• Sodium valproate intake (due to histone deacetylase blockade)
• Viral infections in the first trimester and bacterial infections in the second.

ASD has also been linked to the existence of a greater oxidative stress in some gene-environment interactions.

Other syndromes that have been linked to ASD and DNA methylation are:

• DNA methylation in relation to imprinting and the inactivation process of one of the X chromosomes.

o  DNA methylation is also related to long-distance interactions between chromosomes. and within the same chromosome

• The imprint It is a differential inhibition of gene expression (the imprinted genes are not expressed) depending on their parental origin. "Several studies have demonstrated the role of imprinting in ASD, with Angelman Syndrome being an example of this phenomenon. In this case, a deletion occurs in the 15q11-13 region of the maternal chromosome, while the corresponding paternal allele is silenced. ASD has also been linked to duplication of the 15q11-13 region of the maternal chromosome."¹

Botton line, it has been shown that epigenetic factors  They play a fundamental role in brain development and neurodevelopmental disorders, although much remains to be clarified to establish a sustainable hypothesis regarding the etiology of ASD.

Analysis of the entire epigenome and candidate genes in ASD

It is known in English by the acronym EWAS (Epigenome-wide Analysis scale).

The aim is to find biomarkers in brain regions showing signs of dysregulation. Advances in this line of research are promising, although much remains to be clarified, especially given the opportunities offered by biobanks.

There are several lines of research related to methylation and TEA, using EWAS. 

Model for in vitro epigenetic study: Somatic pluripotent stem cells and brain organoids

The acronym in English is: iPSCs Somatic cells are more useful for research than embryonic cells. They are reprogrammed histiocytes so that they become pluripotent. This pluripotency can be determined in the laboratory. In our case, we are interested in those that develop into nervous tissue, in general and into specific structures. We can achieve this by modifying epigenetic aspects in the laboratory.

The iPSCs maintain the genetic information of the subject from which they originateTherefore, they are also being used in ASD research, using iPSCs from patients, comparing them with unaffected relatives and controls.

A study has revealed excessive neuronal proliferation with an excessive increase in volume. It appears that the cause of this excessive growth is a dysregulation of the transcription cascade of the beta-catenin/BRN2and that defects in neural networks are rescued through the insulin-like growth factor 1.

Cerebral organoids These are aggregates of brain tissue produced in the laboratory through appropriate culturing and programming. We are on the cusp of artificial brains.

The possibilities that organoids offer us The brain scans are impressive, as they not only allow for the introduction of changes to the genome, but also the possibility of comparing the epigenetic aspects of patients with ASD and their relatives without the condition. It will be possible to investigate, without the limitations of postmortem tissue, which dysregulations during prenatal development are involved in ASD.

• Some issues that are currently being addressed:

• Bioethical issues (patents, appropriate legislation to regulate it…)
  • Techniques:
    • Limitations in transport: oxygen, nutrients.
    • Crop-dependent alterations in gene expression.
    • Establishment of standards and reproducibility.
    • It is not yet fully proven that the functions observed in vitro can be compared to those that occur in vivo.

Despite these drawbacks, iPSCs are the future of research that will lead to activities for the prevention, diagnosis and treatment of ASD.

1. Sheena Louise Forsberg et al. 1Epigenetics and cerebral organoids: promising directions in autism spectrum disorders. Translational Psychiatry (2018) 8:14 [↩]