Establishing And Maintaining The Blood-Brain Barrier: Epigenetic And Signaling Determinants

Jayanarayanan Sadanandan; Sithara Thomas; Iny Elizabeth Mathew; Zhen Huang; Spiros L. Blackburn; Nitin Tandon; Hrishikesh Lokhande; Pierre D. McCrea; Emery H. Bresnick; Pramod K. Dash; Devin McBride; Arif Harmanci; Dania Jose; Ari C. Dienel; Hussein A. Zeineddine; Sungha Hong; T. Peeyush Kumar

doi:10.7554/eLife.86978.1

Establishing And Maintaining The Blood-Brain Barrier: Epigenetic And Signaling Determinants

Jayanarayanan Sadanandan, Sithara Thomas, Iny Elizabeth Mathew, Zhen Huang, Spiros L. Blackburn, Nitin Tandon, Hrishikesh Lokhande, Pierre D. McCrea, Emery H. Bresnick, Pramod K. Dash, Devin McBride, Arif Harmanci, Dania Jose, Ari C. Dienel, Hussein A. Zeineddine, Sungha Hong, T. Peeyush Kumar

Genetics

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

Abstract

The blood-brain barrier (BBB) controls the movement of molecules into and out of the central nervous system (CNS). Since a functional BBB forms by mouse embryonic day E15.5, we reasoned that gene cohorts expressed in CNS endothelial cells (EC) at E13.5 contribute to BBB formation, whereas adult gene signatures reflect BBB maintenance mechanisms. Supporting this hypothesis, transcriptomic analysis revealed distinct cohorts of EC genes during BBB formation and maintenance. Here we demonstrate that epigenetic regulator’s histone deacetylase 2 (HDAC2) and polycomb repressive complex 2 (PRC2) control EC gene expression for BBB development and prevented Wnt/β-catenin (Wnt) target genes from being expressed in adult CNS ECs. Low Wnt activity during development modifies BBB genes epigenetically for the formation of functional BBB. As a Class-I HDAC inhibitor induces adult CNS ECs to regain Wnt activity and BBB genetic signatures that support BBB formation, our results inform strategies to promote BBB repair.

Original language	English (US)
Journal	eLife
Volume	12
DOIs	https://doi.org/10.7554/eLife.86978.1
State	Published - 2023

ASJC Scopus subject areas

General Neuroscience
General Biochemistry, Genetics and Molecular Biology
General Immunology and Microbiology

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Sadanandan, J., Thomas, S., Mathew, I. E., Huang, Z., Blackburn, S. L., Tandon, N., Lokhande, H., McCrea, P. D., Bresnick, E. H., Dash, P. K., McBride, D., Harmanci, A., Jose, D., Dienel, A. C., Zeineddine, H. A., Hong, S., & Kumar, T. P. (2023). Establishing And Maintaining The Blood-Brain Barrier: Epigenetic And Signaling Determinants. eLife, 12. https://doi.org/10.7554/eLife.86978.1

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title = "Establishing And Maintaining The Blood-Brain Barrier: Epigenetic And Signaling Determinants",

abstract = "The blood-brain barrier (BBB) controls the movement of molecules into and out of the central nervous system (CNS). Since a functional BBB forms by mouse embryonic day E15.5, we reasoned that gene cohorts expressed in CNS endothelial cells (EC) at E13.5 contribute to BBB formation, whereas adult gene signatures reflect BBB maintenance mechanisms. Supporting this hypothesis, transcriptomic analysis revealed distinct cohorts of EC genes during BBB formation and maintenance. Here we demonstrate that epigenetic regulator{\textquoteright}s histone deacetylase 2 (HDAC2) and polycomb repressive complex 2 (PRC2) control EC gene expression for BBB development and prevented Wnt/β-catenin (Wnt) target genes from being expressed in adult CNS ECs. Low Wnt activity during development modifies BBB genes epigenetically for the formation of functional BBB. As a Class-I HDAC inhibitor induces adult CNS ECs to regain Wnt activity and BBB genetic signatures that support BBB formation, our results inform strategies to promote BBB repair.",

author = "Jayanarayanan Sadanandan and Sithara Thomas and Mathew, {Iny Elizabeth} and Zhen Huang and Blackburn, {Spiros L.} and Nitin Tandon and Hrishikesh Lokhande and McCrea, {Pierre D.} and Bresnick, {Emery H.} and Dash, {Pramod K.} and Devin McBride and Arif Harmanci and Dania Jose and Dienel, {Ari C.} and Zeineddine, {Hussein A.} and Sungha Hong and Kumar, {T. Peeyush}",

year = "2023",

doi = "10.7554/eLife.86978.1",

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AU - Sadanandan, Jayanarayanan

AU - Thomas, Sithara

AU - Mathew, Iny Elizabeth

AU - Huang, Zhen

AU - Blackburn, Spiros L.

AU - Tandon, Nitin

AU - Lokhande, Hrishikesh

AU - McCrea, Pierre D.

AU - Bresnick, Emery H.

AU - Dash, Pramod K.

AU - McBride, Devin

AU - Harmanci, Arif

AU - Jose, Dania

AU - Dienel, Ari C.

AU - Zeineddine, Hussein A.

AU - Hong, Sungha

AU - Kumar, T. Peeyush

PY - 2023

Y1 - 2023

N2 - The blood-brain barrier (BBB) controls the movement of molecules into and out of the central nervous system (CNS). Since a functional BBB forms by mouse embryonic day E15.5, we reasoned that gene cohorts expressed in CNS endothelial cells (EC) at E13.5 contribute to BBB formation, whereas adult gene signatures reflect BBB maintenance mechanisms. Supporting this hypothesis, transcriptomic analysis revealed distinct cohorts of EC genes during BBB formation and maintenance. Here we demonstrate that epigenetic regulator’s histone deacetylase 2 (HDAC2) and polycomb repressive complex 2 (PRC2) control EC gene expression for BBB development and prevented Wnt/β-catenin (Wnt) target genes from being expressed in adult CNS ECs. Low Wnt activity during development modifies BBB genes epigenetically for the formation of functional BBB. As a Class-I HDAC inhibitor induces adult CNS ECs to regain Wnt activity and BBB genetic signatures that support BBB formation, our results inform strategies to promote BBB repair.

AB - The blood-brain barrier (BBB) controls the movement of molecules into and out of the central nervous system (CNS). Since a functional BBB forms by mouse embryonic day E15.5, we reasoned that gene cohorts expressed in CNS endothelial cells (EC) at E13.5 contribute to BBB formation, whereas adult gene signatures reflect BBB maintenance mechanisms. Supporting this hypothesis, transcriptomic analysis revealed distinct cohorts of EC genes during BBB formation and maintenance. Here we demonstrate that epigenetic regulator’s histone deacetylase 2 (HDAC2) and polycomb repressive complex 2 (PRC2) control EC gene expression for BBB development and prevented Wnt/β-catenin (Wnt) target genes from being expressed in adult CNS ECs. Low Wnt activity during development modifies BBB genes epigenetically for the formation of functional BBB. As a Class-I HDAC inhibitor induces adult CNS ECs to regain Wnt activity and BBB genetic signatures that support BBB formation, our results inform strategies to promote BBB repair.

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Establishing And Maintaining The Blood-Brain Barrier: Epigenetic And Signaling Determinants

Abstract

ASJC Scopus subject areas

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