TFEB regulates murine liver cell fate during development and regeneration

Nunzia Pastore; Tuong Huynh; Niculin J. Herz; Alessia Calcagni; Tiemo J. Klisch; Lorenzo Brunetti; Kangho Ho Kim; Marco De Giorgi; Ayrea Hurley; Annamaria Carissimo; Margherita Mutarelli; Niya Aleksieva; Luca D'Orsi; William R. Lagor; David D. Moore; Carmine Settembre; Milton J. Finegold; Stuart Forbes; Andrea Ballabio

doi:10.1038/s41467-020-16300-x

TFEB regulates murine liver cell fate during development and regeneration

Nunzia Pastore, Tuong Huynh, Niculin J. Herz, Alessia Calcagni, Tiemo J. Klisch, Lorenzo Brunetti, Kangho Ho Kim, Marco De Giorgi, Ayrea Hurley, Annamaria Carissimo, Margherita Mutarelli, Niya Aleksieva, Luca D'Orsi, William R. Lagor, David D. Moore, Carmine Settembre, Milton J. Finegold, Stuart Forbes, Andrea Ballabio

Research output: Contribution to journal › Article › peer-review

Abstract

It is well established that pluripotent stem cells in fetal and postnatal liver (LPCs) can differentiate into both hepatocytes and cholangiocytes. However, the signaling pathways implicated in the differentiation of LPCs are still incompletely understood. Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, is known to be involved in osteoblast and myeloid differentiation, but its role in lineage commitment in the liver has not been investigated. Here we show that during development and upon regeneration TFEB drives the differentiation status of murine LPCs into the progenitor/cholangiocyte lineage while inhibiting hepatocyte differentiation. Genetic interaction studies show that Sox9, a marker of precursor and biliary cells, is a direct transcriptional target of TFEB and a primary mediator of its effects on liver cell fate. In summary, our findings identify an unexplored pathway that controls liver cell lineage commitment and whose dysregulation may play a role in biliary cancer.

Original language	English
Article number	2461
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-16300-x
Publication status	Published - 18 May 2020

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Niya Aleksieva AAM - TFEB influences cell fate in developing and adult liver
This is author's final peer-reviewed manuscript as accepted for publication.
Accepted author manuscript, 260 KBLicence: Creative Commons: Attribution Non-Commercial (CC-BY-NC)

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Pastore, N., Huynh, T., Herz, N. J., Calcagni, A., Klisch, T. J., Brunetti, L., Kim, K. H., De Giorgi, M., Hurley, A., Carissimo, A., Mutarelli, M., Aleksieva, N., D'Orsi, L., Lagor, W. R., Moore, D. D., Settembre, C., Finegold, M. J., Forbes, S., & Ballabio, A. (2020). TFEB regulates murine liver cell fate during development and regeneration. Nature Communications, 11(1), [2461]. https://doi.org/10.1038/s41467-020-16300-x

Pastore, Nunzia ; Huynh, Tuong ; Herz, Niculin J. ; Calcagni, Alessia ; Klisch, Tiemo J. ; Brunetti, Lorenzo ; Kim, Kangho Ho ; De Giorgi, Marco ; Hurley, Ayrea ; Carissimo, Annamaria ; Mutarelli, Margherita ; Aleksieva, Niya ; D'Orsi, Luca ; Lagor, William R. ; Moore, David D. ; Settembre, Carmine ; Finegold, Milton J. ; Forbes, Stuart ; Ballabio, Andrea. / TFEB regulates murine liver cell fate during development and regeneration. In: Nature Communications. 2020 ; Vol. 11, No. 1.

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title = "TFEB regulates murine liver cell fate during development and regeneration",

abstract = "It is well established that pluripotent stem cells in fetal and postnatal liver (LPCs) can differentiate into both hepatocytes and cholangiocytes. However, the signaling pathways implicated in the differentiation of LPCs are still incompletely understood. Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, is known to be involved in osteoblast and myeloid differentiation, but its role in lineage commitment in the liver has not been investigated. Here we show that during development and upon regeneration TFEB drives the differentiation status of murine LPCs into the progenitor/cholangiocyte lineage while inhibiting hepatocyte differentiation. Genetic interaction studies show that Sox9, a marker of precursor and biliary cells, is a direct transcriptional target of TFEB and a primary mediator of its effects on liver cell fate. In summary, our findings identify an unexplored pathway that controls liver cell lineage commitment and whose dysregulation may play a role in biliary cancer.",

author = "Nunzia Pastore and Tuong Huynh and Herz, {Niculin J.} and Alessia Calcagni and Klisch, {Tiemo J.} and Lorenzo Brunetti and Kim, {Kangho Ho} and {De Giorgi}, Marco and Ayrea Hurley and Annamaria Carissimo and Margherita Mutarelli and Niya Aleksieva and Luca D'Orsi and Lagor, {William R.} and Moore, {David D.} and Carmine Settembre and Finegold, {Milton J.} and Stuart Forbes and Andrea Ballabio",

year = "2020",

month = may,

day = "18",

doi = "10.1038/s41467-020-16300-x",

language = "English",

volume = "11",

journal = "Nature Communications",

issn = "2041-1723",

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Pastore, N, Huynh, T, Herz, NJ, Calcagni, A, Klisch, TJ, Brunetti, L, Kim, KH, De Giorgi, M, Hurley, A, Carissimo, A, Mutarelli, M, Aleksieva, N, D'Orsi, L, Lagor, WR, Moore, DD, Settembre, C, Finegold, MJ, Forbes, S & Ballabio, A 2020, 'TFEB regulates murine liver cell fate during development and regeneration', Nature Communications, vol. 11, no. 1, 2461. https://doi.org/10.1038/s41467-020-16300-x

TFEB regulates murine liver cell fate during development and regeneration. / Pastore, Nunzia; Huynh, Tuong; Herz, Niculin J.; Calcagni, Alessia; Klisch, Tiemo J.; Brunetti, Lorenzo; Kim, Kangho Ho; De Giorgi, Marco; Hurley, Ayrea; Carissimo, Annamaria; Mutarelli, Margherita; Aleksieva, Niya; D'Orsi, Luca; Lagor, William R.; Moore, David D.; Settembre, Carmine; Finegold, Milton J.; Forbes, Stuart; Ballabio, Andrea.

In: Nature Communications, Vol. 11, No. 1, 2461, 18.05.2020.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - TFEB regulates murine liver cell fate during development and regeneration

AU - Pastore, Nunzia

AU - Huynh, Tuong

AU - Herz, Niculin J.

AU - Calcagni, Alessia

AU - Klisch, Tiemo J.

AU - Brunetti, Lorenzo

AU - Kim, Kangho Ho

AU - De Giorgi, Marco

AU - Hurley, Ayrea

AU - Carissimo, Annamaria

AU - Mutarelli, Margherita

AU - Aleksieva, Niya

AU - D'Orsi, Luca

AU - Lagor, William R.

AU - Moore, David D.

AU - Settembre, Carmine

AU - Finegold, Milton J.

AU - Forbes, Stuart

AU - Ballabio, Andrea

PY - 2020/5/18

Y1 - 2020/5/18

N2 - It is well established that pluripotent stem cells in fetal and postnatal liver (LPCs) can differentiate into both hepatocytes and cholangiocytes. However, the signaling pathways implicated in the differentiation of LPCs are still incompletely understood. Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, is known to be involved in osteoblast and myeloid differentiation, but its role in lineage commitment in the liver has not been investigated. Here we show that during development and upon regeneration TFEB drives the differentiation status of murine LPCs into the progenitor/cholangiocyte lineage while inhibiting hepatocyte differentiation. Genetic interaction studies show that Sox9, a marker of precursor and biliary cells, is a direct transcriptional target of TFEB and a primary mediator of its effects on liver cell fate. In summary, our findings identify an unexplored pathway that controls liver cell lineage commitment and whose dysregulation may play a role in biliary cancer.

AB - It is well established that pluripotent stem cells in fetal and postnatal liver (LPCs) can differentiate into both hepatocytes and cholangiocytes. However, the signaling pathways implicated in the differentiation of LPCs are still incompletely understood. Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, is known to be involved in osteoblast and myeloid differentiation, but its role in lineage commitment in the liver has not been investigated. Here we show that during development and upon regeneration TFEB drives the differentiation status of murine LPCs into the progenitor/cholangiocyte lineage while inhibiting hepatocyte differentiation. Genetic interaction studies show that Sox9, a marker of precursor and biliary cells, is a direct transcriptional target of TFEB and a primary mediator of its effects on liver cell fate. In summary, our findings identify an unexplored pathway that controls liver cell lineage commitment and whose dysregulation may play a role in biliary cancer.

U2 - 10.1038/s41467-020-16300-x

DO - 10.1038/s41467-020-16300-x

M3 - Article

VL - 11

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 2461

ER -

TFEB regulates murine liver cell fate during development and regeneration

Abstract

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