Enhanced Expression of Human Endogenous Retroviruses, TRIM28 and SETDB1 in Autism Spectrum Disorder

Abstract

Human endogenous retroviruses (HERVs) are relics of ancestral infections and represent 8% of the human genome. They are no longer infectious, but their activation has been associated with several disorders, including neuropsychiatric conditions. Enhanced expression of HERV-K and HERV-H envelope genes has been found in the blood of autism spectrum disorder (ASD) patients, but no information is available on syncytin 1 (SYN1), SYN2, and multiple sclerosis-associated retrovirus (MSRV), which are thought to be implicated in brain development and immune responses. HERV activation is regulated by TRIM28 and SETDB1, which are part of the epigenetic mechanisms that organize the chromatin architecture in response to external stimuli and are involved in neural cell differentiation and brain inflammation. We assessed, through a PCR realtime Taqman amplification assay, the transcription levels of pol genes of HERV-H, -K, and -W families, of env genes of SYN1, SYN2, and MSRV, as well as of TRIM28 and SETDB1 in the blood of 33 ASD children (28 males, median 3.8 years, 25–75% interquartile range 3.0–6.0 y) and healthy controls (HC). Significantly higher expressions of TRIM28 and SETDB1, as well as of all the HERV genes tested, except for HERV-W-pol, were found in ASD, as compared with HC. Positive correlations were observed between the mRNA levels of TRIM28 or SETDB1 and every HERV gene in ASD patients, but not in HC. Overexpression of TRIM28/SETDB1 and several HERVs in children with ASD and the positive correlations between their transcriptional levels suggest that these may be main players in pathogenetic mechanisms leading to ASD.

An old model with new insights: endogenous retroviruses drive the evolvement toward ASD susceptibility and hijack transcription machinery during development

“…Therefore, this clinical evidence supports our hypothesis that active ERV associated with retrotransposition can disperse ERV copies throughout the genome and increase the chance of CNV formation in the two BTBR strains. Of note, enhanced HERV expressions in individuals with ASD have been reported by multiple groups [79,80]. Taken together with the demonstrated roles of ERV in CNV formation, our observation of the two BTBR strains provides a vivid model to describe how the genome evolves toward ASD susceptibility.…”

Susceptibility and resilience to maternal immune activation are associated with differential expression of endogenous retroviral elements

“…The rationale underlying the selection of the class II murine ERVs was twofold. First, they are phylogenetically related to the human ERV-K (HERV-K) elements (Stocking and Kozak, 2008), which in turn have been found to be increased in various psychiatric and neurodevelopmental disorders, including schizophrenia (Frank et al, 2005;Slokar and Hasler, 2016), bipolar disorder (Frank et al, 2005) and ASD (Tovo et al, 2022). Second, high expression of class II murine ERVs has been found in two mouse models relevant for ASD (Cipriani et al, 2018b), suggesting that they may play a role in altering brain development and functions implicated in ASD.…”

Pregnancy Is Associated with Impaired Transcription of Human Endogenous Retroviruses and of TRIM28 and SETDB1, Particularly in Mothers Affected by Multiple Sclerosis

“…Relative quantification of transcription levels of pol genes of HERV-H, HERV-K, and HERV-W; of env genes of SYN1, SYN2, and MSRV; and of TRIM28 and SETDB1 were achieved as previously described in detail [ 46 , 81 , 82 , 83 ] using the primers and probes reported in Table 1 . Briefly, 40 ng of cDNA was amplified in a 20 μL total volume reaction, containing 2.5 U goTaQ MaterMix (Promega), 1.25 mmol/L MgCl 2 , 500 nmol of specific primers, and 200 nmol of specific probes.…”

“…Syncytins and a HERV- env protein have potent intrinsic immunomodulatory properties [ 31 , 32 , 40 ]. Several lines of research have evidenced an association between aberrant HERV expressions and autoimmune diseases [ 35 , 41 , 42 , 43 ] and neurologic disorders [ 44 , 45 , 46 , 47 ]. A strong correlation has been found between enhanced expression of all HERV families studied and onset and progression of MS [ 48 , 49 , 50 , 51 ].…”