The m6A profile of human Arcuate nucleus-specific organoids (ARCOs)
m6A, the most prevalent internal modification on mRNAs, plays important roles in the nervous system. Whether neurogenesis in the hypothalamus, a region critical for controlling appetite, is regulated by m6A signaling, especially in humans, remains unclear. Here we showed that deletion of m6A writer Mettl14 in the mouse embryonic hypothalamus led to adult obesity, with impaired glucose-insulin homoeostasis and increased energy intake. Mechanistically, deletion of Mettl14 leads to hypothalamic arcuate nucleus neurogenesis deficits with reduced generation of feeding-related neurons and dysregulation of neurogenesis-related m6A-tagged transcripts. Deletion of m6A writer Mettl3, or m6A reader Ythdc1, shared similar phenotypes. METTL14 or YTHDC1 knockdown also led to reduced generation of feeding-related neurons in human brain subregion-specific arcuate nucleus organoids. Our studies reveal a conserved role of m6A signaling in arcuate nucleus neurogenesis in mice and human organoids and shed light on the developmental basis of epitranscriptomic regulation of food intake and energy homeostasis. Overall design: m6A sequencing of day 12 induced human arcuate nucleus-specific organoids (ARCOs) from iPSCs