As many on our listserve are aware, I have been proposing that the ‘genetics’ of severe mental illness may very well be found in epigenetics (please note: I am not proposing that such a complex human illness as the schizophrenias can be explained or understood through genetics or neurobiology apart from the relational and sociocultural surround) as well as proteomics rather than traditional classical genomic ‘errors’ in the genetic code (i.e., sequencing errors leading to the coding of ‘dysfunctional’ proteins). As noted by Arturas Petronis (2004): “By definition, epigenetics refers to regulation of gene expressions that are controlled by heritable but potentially reversible changes in DNA methylation and/or chromatin structure” (p.175-in “Schizophrenia, neurodevelopment, and epigenetics” in Neurodevelopment and Schizophrenia, edited by Matcheri Keshavan, James Kennedy & Robin Murray in 2004 for Cambridge University Press).
Etymologically, the term epigenetics originated from the term epigenesis, a theory of development which proposed that the embryo at early stages is not differentiated and that embryogenesis proceeds by increasing levels of complexity. C. H. Waddington coined the term epigenetics in the 1950s, and it referred to the way developmental processes connected the genotype with phenotype. Waddington spoke of an “epigenetic landscape” which was a simplified version of the “multidimensional and intricate non-linear interactions of various molecules within the cell during the embryonic development” (p.180, Petronis 2004). Although direct proof of the role of epigenetics in development is not available, epigenetic regulation may serve as a candidate for the mechanistic explanation of cell differentiation and development..
A large number of genes exhibit an inverse correlation between the degree of methylation and gene expression, which lends support to an increasing body of experimental evidence suggesting that epigenetic modification is closely involved in the regulation of the expression of genes. One of the processes of epigenetic regulation of genes is related to methylation of the binding sites of transcription factors, leading to a change in the affinity of these factors for the regulatory sequences of these specific genes. This seems to be linked to another type of epigenetic regulation, that is, various types of histone modification. DNA is wrapped around histone complexes to form nucleosomes-depending on DNA and histone modifications, chromatin can be transcriptionally competent or not. Transcriptionally competent chromatin is normally enriched with acetylated histones, while transcriptionally silent chromatin is deacetylated. The interaction of DNA methylation and histone acetylation shows that the two types of epigenetic regulation act in concert. Epigenetic factors play a role in DNA mutagenesis and repair as well as in DNA recombination and possibly replication. Epigenetic patterns are transmitted similarly to DNA sequences, from maternal chromatids to daughter chromatids during mitotic divisions, and transmission of this epigenetic status is termed the “epigenetic inheritance system.” Unlike DNA sequences, which exhibit almost complete interclonal fidelity, epigentics usually exhibits only partial stability. The partial stability of epigenetic modification is termed “epigenetic metastability.” There is evidence that some epigenetic signals escape erasure during maturation of gametes and, importantly, can be transmitted across generation (inducible defenses against predatory threat, as in the transgenerational transmission of trauma?).
Two key aspects of epigenetic modification of the genome make epigentics very relevant to schizophrenia. First, epigenetic modifications of DNA and chromatin orchestrate the activities of the genome, including regulation of gene expression. Epigenetic metastability is the second key aspect of relevance to schizophrenia. Epigenetic regulation of genes undergoes significant reorganization during development and aging as well as under the influence of extracellular factors (e.g., the hormonal status of the organism-cortisol expression during times of threat?) or environmental factors. Epigenetic regulation represents the dynamic feature of a gene and genome, whereas most of the DNA sequences do not alter during the life of the individual. Time of onset of schizophrenia may correlate with major hormonal (in particular cortisol hormonal expression) rearrangements in the individual. Epigenetic status of the gene is one of the targets of hormone action. Various hormones have a significant impact on gene expression, and this is secured by changing chromatin conformation and/or local patterns of gene methylation. A disease process may be initiated by hormone (e.g., cortisol)-mediated epigenetic changes in critical genes.
Because of its enormous complexity, the human brain is likely to be susceptible to even mild epigenetic malfunction, which might lead to a wide variety of small morphological and functional changes in the developing brain. Epigenetic aberrations (epimutations) may originate from the following sources acting individually or in concert: epimutations, because of epigenetic metastability, can be inherited through the germline; epimutations can be caused by environmental factors; epigenetic aberrations may be generated by stochastic events in the embryonic cells.
For the more reductionistically-oriented researchers in epigenetics, the key question is whether abnormally expressed genes can bring about problematic neurodevelopment. Personally, I take seriously the survival value of intersubjectivity, i.e., in particular in relationship to schizophrenia, I propose that one’s sense of personal existence or non-existence, is significantly dependent on the needed resonance from the human interpersonal surround (there is an interesting account of Paul MacLean meeting with the neuroanatomist Papez, of limbic system fame -- the “Papez circuit”, at his lab at Cornell University, in which MacLean asked Papez what did he think was the neural basis of our sense of subjectivity. Papez immediately replied “resonance”), and that many psychotic symptoms, such as hallucinations, self-referential thinking and delusions, are the individual’s attempts to maintain homeostatic equilibrium and a sense of personal existence and worthwhileness, when that particular individual has not achieved the developmental processes/structures which confer a sense of going-on-of-being, a positively toned sense of self-other, as well as having the right to be, within relational and cultural contexts.
Brian Koehler
New York University
I am including previous relevant postings below.
New Direction in Genetic Research in Schizophrenia
Most genetic researchers in schizophrenia believe that there is substantial evidence that this group of disorders involves mutations in the nucleotide sequence of several genes, resulting in abnormal messenger ribonucleic acid (mRNA) (transcription) and therefore abnormal proteins (translation). However, nongenetic factors such as stress, social environment, learning etc., can also modify the expression of a protein by altering the transcription of normal genes. This epigenetic regulation may contribute to the etiology of the schizophrenias. It is proteins that ultimately define the functioning of brain cells, and protein expression can be regulated by epigenetic processes. Pesold, Roberts and Kirkpatrick (2004) noted: “Measuring proteins or the transcripts that encode them may therefore be fruitful in fully understanding the pathology of schizophrenia” (p. 273 in Textbook of Biological Psychiatry edited by Jaak Panksepp and published by Wiley-Liss).
As I pointed out in previous postings, micro-array analysis simultaneously can compare relative levels of thousands of gene transcripts in postmortem tissue. This technology is fairly recent and is now being applied to persons having been diagnosed with schizophrenia. The studies already conducted (Mirnics et al 2001-Analysis of complex brain disorders with gene expression microassays: Schizophrenia as a disease of the synapse. Trends in Neuroscience 24:479-486) have revealed changes in the expression of gene transcripts with developmental relevance including transcription factors, receptors, genes important for myelination, as well as a host of proteins involved in synaptic functioning and neurotransmission.
I think this research on gene expression will one day contribute to the growing awareness of the importance of the environment, in particular, the social and relational environment, in the neurobiology of severe mental illness. Affective processes may then be given greater attention in terms of etiology. My own view is that the schizophrenias are emotionally based disorders (affective disorders with secondary cognitive alterations-much as Luc Ciompi has described in his volume and papers on affect-logic). As Jaak Panksepp (2004), neuroscientist and author of Affective Neuroscience by Oxford University Press, noted in his recent edited volume Textbook of Biological Psychiatry: "A fuller recognition of basic emotional imbalances of many psychiatric disorders may also help reverse a growing problem of modern psychiatry-the marginalization of patients by making them mere consumers of pills rather than agents in reconstructing meaningful human relationships and life insights...perhaps through some type of Meyerian 'sociopsychobiological' synthesis. Obviously, psychiatric disorders will continue to be permeated and modified by hosts of meta-emotional factors-above all, individual capacities for affective self-regulation and thoughtfulness" (pp. 18-19).
Brian Koehler PhD
New York University
80 East 11th Street #339
New York NY 10003
212.533.5687
brian_koehler@psychoanalysis.net
