LSD1 represses a neonatal/reparative gene program in adult intestinal epithelium

R.T. Zwiggelaar; H.T. Lindholm; M. Fosslie; M.T. Pedersen; Y. Ohta; A. Díez-Sánchez; M. Martín-Alonso; J. Ostrop; M. Matano; N. Parmar; E. Kvaløy; R.R. Spanjers; K. Nazmi; M. Rye; F. Drabløs; C. Arrowsmith; J.A. Dahl; K.B. Jensen; T. Sato; M.J. Oudhoff

doi:10.1126/sciadv.abc0367

LSD1 represses a neonatal/reparative gene program in adult intestinal epithelium

R.T. Zwiggelaar, H.T. Lindholm, M. Fosslie, M.T. Pedersen, Y. Ohta, A. Díez-Sánchez, M. Martín-Alonso, J. Ostrop, M. Matano, N. Parmar, E. Kvaløy, R.R. Spanjers, K. Nazmi, M. Rye, F. Drabløs, C. Arrowsmith, J.A. Dahl, K.B. Jensen, T. Sato, M.J. Oudhoff

Oral Biochemistry

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Abstract

Intestinal epithelial homeostasis is maintained by adult intestinal stem cells, which, alongside Paneth cells, appear after birth in the neonatal period. We aimed to identify regulators of neonatal intestinal epithelial development by testing a small library of epigenetic modifier inhibitors in Paneth cell–skewed organoid cultures. We found that lysine-specific demethylase 1A (Kdm1a/Lsd1) is absolutely required for Paneth cell differentiation. Lsd1-deficient crypts, devoid of Paneth cells, are still able to form organoids without a requirement of exogenous or endogenous Wnt. Mechanistically, we find that LSD1 enzymatically represses genes that are normally expressed only in fetal and neonatal epithelium. This gene profile is similar to what is seen in repairing epithelium, and we find that Lsd1-deficient epithelium has superior regenerative capacities after irradiation injury. In summary, we found an important regulator of neonatal intestinal development and identified a druggable target to reprogram intestinal epithelium toward a reparative state.

Original language	English
Article number	eabc0367
Number of pages	14
Journal	Science advances
Volume	6
Issue number	37
DOIs	https://doi.org/10.1126/sciadv.abc0367
Publication status	Published - 11 Sept 2020

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Zwiggelaar, R. T., Lindholm, H. T., Fosslie, M., Pedersen, M. T., Ohta, Y., Díez-Sánchez, A., Martín-Alonso, M., Ostrop, J., Matano, M., Parmar, N., Kvaløy, E., Spanjers, R. R., Nazmi, K., Rye, M., Drabløs, F., Arrowsmith, C., Dahl, J. A., Jensen, K. B., Sato, T., & Oudhoff, M. J. (2020). LSD1 represses a neonatal/reparative gene program in adult intestinal epithelium. Science advances, 6(37), [eabc0367]. https://doi.org/10.1126/sciadv.abc0367

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title = "LSD1 represses a neonatal/reparative gene program in adult intestinal epithelium",

abstract = "Intestinal epithelial homeostasis is maintained by adult intestinal stem cells, which, alongside Paneth cells, appear after birth in the neonatal period. We aimed to identify regulators of neonatal intestinal epithelial development by testing a small library of epigenetic modifier inhibitors in Paneth cell–skewed organoid cultures. We found that lysine-specific demethylase 1A (Kdm1a/Lsd1) is absolutely required for Paneth cell differentiation. Lsd1-deficient crypts, devoid of Paneth cells, are still able to form organoids without a requirement of exogenous or endogenous Wnt. Mechanistically, we find that LSD1 enzymatically represses genes that are normally expressed only in fetal and neonatal epithelium. This gene profile is similar to what is seen in repairing epithelium, and we find that Lsd1-deficient epithelium has superior regenerative capacities after irradiation injury. In summary, we found an important regulator of neonatal intestinal development and identified a druggable target to reprogram intestinal epithelium toward a reparative state.",

author = "R.T. Zwiggelaar and H.T. Lindholm and M. Fosslie and M.T. Pedersen and Y. Ohta and A. D{\'i}ez-S{\'a}nchez and M. Mart{\'i}n-Alonso and J. Ostrop and M. Matano and N. Parmar and E. Kval{\o}y and R.R. Spanjers and K. Nazmi and M. Rye and F. Drabl{\o}s and C. Arrowsmith and J.A. Dahl and K.B. Jensen and T. Sato and M.J. Oudhoff",

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Zwiggelaar, RT, Lindholm, HT, Fosslie, M, Pedersen, MT, Ohta, Y, Díez-Sánchez, A, Martín-Alonso, M, Ostrop, J, Matano, M, Parmar, N, Kvaløy, E, Spanjers, RR, Nazmi, K, Rye, M, Drabløs, F, Arrowsmith, C, Dahl, JA, Jensen, KB, Sato, T & Oudhoff, MJ 2020, 'LSD1 represses a neonatal/reparative gene program in adult intestinal epithelium', Science advances, vol. 6, no. 37, eabc0367. https://doi.org/10.1126/sciadv.abc0367

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T1 - LSD1 represses a neonatal/reparative gene program in adult intestinal epithelium

AU - Zwiggelaar, R.T.

AU - Lindholm, H.T.

AU - Fosslie, M.

AU - Pedersen, M.T.

AU - Ohta, Y.

AU - Díez-Sánchez, A.

AU - Martín-Alonso, M.

AU - Ostrop, J.

AU - Matano, M.

AU - Parmar, N.

AU - Kvaløy, E.

AU - Spanjers, R.R.

AU - Nazmi, K.

AU - Rye, M.

AU - Drabløs, F.

AU - Arrowsmith, C.

AU - Dahl, J.A.

AU - Jensen, K.B.

AU - Sato, T.

AU - Oudhoff, M.J.

PY - 2020/9/11

Y1 - 2020/9/11

N2 - Intestinal epithelial homeostasis is maintained by adult intestinal stem cells, which, alongside Paneth cells, appear after birth in the neonatal period. We aimed to identify regulators of neonatal intestinal epithelial development by testing a small library of epigenetic modifier inhibitors in Paneth cell–skewed organoid cultures. We found that lysine-specific demethylase 1A (Kdm1a/Lsd1) is absolutely required for Paneth cell differentiation. Lsd1-deficient crypts, devoid of Paneth cells, are still able to form organoids without a requirement of exogenous or endogenous Wnt. Mechanistically, we find that LSD1 enzymatically represses genes that are normally expressed only in fetal and neonatal epithelium. This gene profile is similar to what is seen in repairing epithelium, and we find that Lsd1-deficient epithelium has superior regenerative capacities after irradiation injury. In summary, we found an important regulator of neonatal intestinal development and identified a druggable target to reprogram intestinal epithelium toward a reparative state.

AB - Intestinal epithelial homeostasis is maintained by adult intestinal stem cells, which, alongside Paneth cells, appear after birth in the neonatal period. We aimed to identify regulators of neonatal intestinal epithelial development by testing a small library of epigenetic modifier inhibitors in Paneth cell–skewed organoid cultures. We found that lysine-specific demethylase 1A (Kdm1a/Lsd1) is absolutely required for Paneth cell differentiation. Lsd1-deficient crypts, devoid of Paneth cells, are still able to form organoids without a requirement of exogenous or endogenous Wnt. Mechanistically, we find that LSD1 enzymatically represses genes that are normally expressed only in fetal and neonatal epithelium. This gene profile is similar to what is seen in repairing epithelium, and we find that Lsd1-deficient epithelium has superior regenerative capacities after irradiation injury. In summary, we found an important regulator of neonatal intestinal development and identified a druggable target to reprogram intestinal epithelium toward a reparative state.

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DO - 10.1126/sciadv.abc0367

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SN - 2375-2548

VL - 6

JO - Science advances

JF - Science advances

IS - 37

M1 - eabc0367

ER -

LSD1 represses a neonatal/reparative gene program in adult intestinal epithelium

Abstract

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