Maf family transcription factors are required for nutrient uptake in the mouse neonatal gut

There are fundamental differences in how neonatal and adult intestines absorb nutrients. In adults, macromolecules are broken down into simpler molecular components in the lumen of the small intestine, then absorbed. In contrast, neonates are thought to rely on internalization of whole macromolecules and subsequent degradation in the lysosome. Here, we identify the Maf family transcription factors MAFB and c-MAF as markers of terminally differentiated intestinal enterocytes throughout life. The expression of these factors is regulated by HNF4 alpha and HNF4 gamma, master regulators of enterocyte cell fate. Loss of Maf factors results in a neonatal-specific failure to thrive and loss of macromolecular nutrient uptake. RNA-Seq and CUT & RUN analyses defined an endo-lysosomal program as being downstream of these transcription factors. We demonstrate major transcriptional changes in metabolic pathways, including fatty acid oxidation and increases in peroxisome number, in response to loss of Maf proteins. Finally, we show that loss of BLIMP1, a repressor of adult enterocyte genes, shows highly overlapping changes in gene expression and similar defects in macromolecular uptake. This work defines transcriptional regulators that are necessary for nutrient uptake in neonatal enterocytes.

Automated summary

This study identifies MAFB and c-MAF as markers of terminally differentiated intestinal enterocytes and reveals their regulation by HNF4 alpha and HNF4 gamma. Loss of Maf factors leads to neonatal-specific failure to thrive and loss of macromolecular nutrient uptake. The researchers also demonstrate major transcriptional changes in metabolic pathways and an increase in peroxisome number in response to loss of Maf proteins. Additionally, loss of BLIMP1 shows similar changes in gene expression and defects in macromolecular uptake.