Early-Life mA RNA Demethylation by Fat Mass and Obesity-Associated Protein (FTO) Influences Resilience or Vulnerability to Heat Stress Later in Life.

Early life heat stress leads to either resilience or vulnerability to a similar stress later in life. We have previously shown that this tuning of the stress response depends on neural network organization in the preoptic anterior hypothalamus (PO/AH) thermal response center and is regulated by epigenetic mechanisms. Here, we expand our understanding of stress response establishment describing a role for epitranscriptomic regulation of the epigenetic machinery. Specifically, we explore the role of N-methyladenosine (mA) RNA methylation in long-term response to heat stress. Heat conditioning of 3-d-old chicks diminished mA RNA methylation in the hypothalamus, simultaneously with an increase in the mRNA levels of the mA demethylase, fat mass and obesity-associated protein (). Moreover, a week later, methylation of two heat stress-related transcripts, histone 3 lysine 27 (H3K27) methyltransferase, enhancer of zeste homolog 2 () and brain-derived neurotrophic factor (), were downregulated in harsh-heat-conditioned chicks. During heat challenge a week after conditioning, there was a reduction of mA levels in mild-heat-conditioned chicks and an elevation in harsh-heat-conditioned ones. This increase in mA modification was negatively correlated with the expression levels of both and Antisense "knock-down" of FTO caused an elevation of global mA RNA methylation, reduction of and mRNA levels, and decrease in global H3K27 dimethylation as well as dimethyl H3K27 level along coding region, and, finally, led to heat vulnerability. These findings emphasize the multilevel regulation of gene expression, including both epigenetic and epitranscriptomic regulatory mechanisms, fine-tuning the neural network organization in a response to stress.