Understanding the transgenerational epigenetic effect of maternal psychosocial trauma exposure on infants via lncRNA-sequencing - SUMMARY PROJECT
This collaborative project, between McLean Hospital, Harvard Medical School, USA and Cape Town
University, South Africa, proposes to investigate the biological mechanisms underlying effects of maternal
stress on infant development. Prospective, longitudinal, mother-child cohort studies have found that children
exposed to maternal psychological stress, depression, or anxiety during the prenatal period have higher risk for
behavioral and emotional problems later in life, including increased fearfulness, anxiety, and depression. We
propose to examine RNA-mediated epigenetic factors in this proposal. We recently found that adults with
comorbid PTSD and/or Depression (PTSD/MDD) have reduced expression of the DICER1 gene, which plays a
central role in stress-related pathways by controlling ncRNA expression. Additional new work from our group
has shown differential expression of a long non-coding RNA (lncRNA), GAS5, which directly regulates
glucocorticoid receptor sensitivity, in recently traumatized adults as a predictor of later PTSD development.
lncRNAs regulate expression of more than half of all protein-coding genes post-transcriptionally in the body.
This study will extend our adult PTSD findings of DICER1, GAS5 and other lncRNA pathways, to elucidate
mechanisms underlying transmission of risk across generations using an integrative developmental model in
the Drakenstein mother/infant cohort. In aim 1, we will focus on in utero developmental RNA profiles. We will
examine lncRNA and lncRNA-mediated epigenetic effects at birth, in infants exposed in utero to maternal
PTSD/MDD by investigating RNAs that are altered in both mothers with PTSD/MDD and their infants in the
Drakenstein mother/infant cohort (N=450). In aim 2, we will focus on early life developmental RNA profiles. We
will examine longitudinal stability of lncRNA-mediated epigenetic factors associated with exposure to maternal
PTSD/MDD at birth and at age 2 and 5 years. We will identify lncRNA-based factors that are persistently
altered in exposed infants at birth across age 5 to elucidate the effects of maternal stress during early life
development, which may prelude to manifestation of negative outcomes later in life. In aim 3, we will focus on
early life RNA profiles and subsequent behavioral-developmental outcomes. We will identify the effects of RNA
profiles at birth, age 2 and 5 years on behavioral and developmental measures at ages 2, 3.5 and 5 years. In
utero and environmentally induced changes in expression levels of RNA-mediated epigenetic factors may
predict development of behavioral and emotional problems. Through each of these aims, the proposal will build
research capacity through training, site visits, collaborative data analyses, publications, and presentations.
Through collaboration between the low- and middle-income country (LMIC) and upper- and middle-income
country (UMIC) institutions we will lay foundation via infrastructure and collection of unique phenotypes and
RNA-sequencing data for future studies of this unique mother-child cohort in the LMIC, advancing our
understanding of risk and child development.
