PRC2 Regulated Atoh8 Is a Regulator of Intestinal Microfold Cell (M Cell) Differentiation

Abstract

Intestinal microfold cells (M cells) are a dynamic lineage of epithelial cells that initiate mucosal immunity in the intestine. They are responsible for the uptake and transcytosis of microorganisms, pathogens, and other antigens in the gastrointestinal tract. A mature M cell expresses a receptor Gp2 which binds to pathogens and aids in the uptake. Due to the rarity of these cells in the intestine, their development and differentiation remain yet to be fully understood. We recently demonstrated that polycomb repressive complex 2 (PRC2) is an epigenetic regulator of M cell development, and 12 novel transcription factors including Atoh8 were revealed to be regulated by the PRC2. Here, we show that Atoh8 acts as a regulator of M cell differentiation; the absence of Atoh8 led to a significant increase in the number of Gp2+ mature M cells and other M cell-associated markers such as Spi-B and Sox8. In vitro organoid analysis of RankL treated organoid showed an increase of mature marker GP2 expression and other M cell-associated markers. Atoh8 null mice showed an increase in transcytosis capacity of luminal antigens. An increase in M cell population has been previously reported to be detrimental to mucosal immunity because some pathogens like orally acquired prions have been able to exploit the transcytosis capacity of M cells to infect the host; mice with an increased population of M cells are also susceptible to Salmonella infections. Our study here demonstrates that PRC2 regulated Atoh8 is one of the factors that regulate the population density of intestinal M cell in the Peyer’s patch.

Intestinal Peyer’s Patches: Structure, Function, and In Vitro Modeling

“…The RANKL binding to RANK on the stem cells induces the expression of SpiB and Sox8, which are key transcription factors involved in M cell differentiation [ 12 – 14 ]. Another important transcription factor, Atoh8, controls the density of M cell population in FAE and is regulated by polycomb repressive complex 2 (PRC2), which is an epigenetic regulator of M cell development [ 15 , 16 ]. M cells are also differentiated from enterocytes under the influence of membrane-bound lymphotoxin (LTα1β2) present on local lymphoid cells, mainly B cells.…”

Atoh8 in Development and Disease

“…Iron plays a crucial role in bacterial growth, overloading of iron leads to a significant increase in gut microbiota resulting in inflammation. It is logical to think that the increase in the number of M-Cells in the case of Atoh8 knockout mice could be a compensatory mechanism adapted by these animals to counter prolonged bacterial infections [ 65 , 66 ].…”

Epigenetic modulators of B cell fate identified through coupled phenotype-transcriptome analysis

“…S4f, i, Supplementary Table 2), suggesting a bona fide relationship between genes associated with ASC differentiation and novel genes such as Atoh8 identified in this study. Additionally, a recent study by George et al showed that Atoh8 acts as a regulator of M cell differentiation by inhibiting Spi-B [25]. Spi-B is a negative regulator of ASC differentiation and ASC differentiation is increased in mice deficient of Spi-B [26,27].…”