Perinatal protein malnutrition results in genome-wide disruptions of 3 5-hydroxymethylcytosine at regions that can be restored to control levels by an enriched environment

CAROLINA ALBERCA; LIGIA A. PAPALE; ANDY MADRID; GIANATIEMPO, OCTAVIO; EDUARDO T. CÁNEPA; REID S. ALISCH; MARIELA CHERTOFF

EPIGENETICS

LANDES BIOSCIENCE

Lugar: Austin, Texas; Año: 2020

1559-2294

Maternal malnutrition remains one of the major adversities affecting brain development47 and long-term mental health outcomes, increasing the risk to develop anxiety and depressive48 disorders. We have previously shown that malnutrition-induced anxiety-like behaviors can be49 rescued by a social and sensory stimulation (enriched environment) in male mice. Here, we50 expand these findings to adult female mice and profiled genome-wide ventral hippocampal51 5hmC levels related to malnutrition-induced anxiety-like behaviors and their rescue by an52 enriched environment. This approach revealed 508 differentially hydroxymethylated genes53 associated with protein malnutrition and that several genes (N = 34) exhibited a restored 5hmC54 abundance to control levels following exposure to an enriched environment, including genes55 involved in neuronal functions like dendrite outgrowth, axon guidance, and maintenance of56 neuronal circuits (e.g., Fltr3, Itsn1, Lman1, Lsamp, Nav, and Ror1) and epigenetic mechanisms57 (e.g., Hdac9 and Dicer1). Sequence motif predictions indicated that 5hmC may be modulating58 the binding of transcription factors for several of these transcripts, suggesting a regulatory role59 for 5hmC in response to perinatal malnutrition and exposure to an enriched environment.60 Together, these findings establish a role for 5hmC in early-life malnutrition and reveal genes61 linked to malnutrition-induced anxious behaviors that are mitigated by an enriched environment