# Examining how the spatial partitioning of metabolism underlies cell state

> **NIH NIH R35** · CHILDREN'S HOSP OF PHILADELPHIA · 2022 · $440,000

## Abstract

Project Summary
Multicellular development requires extensive cell-cell interactions and transcriptional reprogramming
accomplished at the level of chromatin remodeling. These processes are classically understood to entail the
transmission of information from outside a cell to its nucleus, however this paradigm largely overlooks the fact
that biology involves the movement of biochemical information across spaces beyond the plasma membrane and
the nuclear envelope. Unlike prokaryotes, in which transcription and metabolism occur in the same membrane-
bound compartment, multicellular eukaryotes partition their metabolism and biochemistry at multiple layers:
amongst the organelles within a cell, between cells within a tissue, and throughout the organ systems that compose
a host. We hypothesize that the spatial partitioning of biochemistry, through cellular metabolism, regulates cell
development and function by controlling histone epigenetics and coordinating interacting cells within tissues.
We have recently shown that metabolic crosstalk between the mitochondria and cytosol is an essential component
of cell differentiation and set out to extend this paradigm to explore how the movement of metabolites across
between cellular and tissue compartments dictates their biology. We seek to explore this at two levels: 1)
elucidating the molecular mechanism explaining how mitochondrial-cytosolic crosstalk controls histone
epigenetics; 2) investigating how cell-cell metabolite exchange influences development and coordinates responses
between interacting populations of cells. We will explore these concepts in the context of the hematopoietic
system, as its development requires extensive epigenetic remodeling, with each lineage and functional program
now understood to be supported by a unique metabolic signature, making it an ideal model system for us to pursue
these studies. This will be accomplished by taking advantage a CRISPR screening system we have developed that
is compatible with nearly every population of primary hematopoietic cells. We will conduct both in vitro and in
vivo unpooled and pooled, barcoded CRISPR screens evaluating all 77 genes encoding mitochondrial transporters
as well as all plasma membrane transporters, to investigate how these metabolic transport systems impact
epigenetic remodeling and development. These studies will be furthered by tandem sgRNA studies that will allow
us to test the epigenetic remodeling enzymes downstream of the metabolic processes we are studying as well as
a combinatorial reverse genetic approach in which different genes in the same network will be targeted in different
populations of interacting cells, allowing us to map metabolic flow in trans. Altogether these studies will not only
help establish a novel paradigm with which to approach molecular biology, but also provide fundamental
mechanistic insights into gene regulation and development.

## Key facts

- **NIH application ID:** 10465131
- **Project number:** 5R35GM138085-03
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Will H. Bailis
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $440,000
- **Award type:** 5
- **Project period:** 2020-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10465131

## Citation

> US National Institutes of Health, RePORTER application 10465131, Examining how the spatial partitioning of metabolism underlies cell state (5R35GM138085-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10465131. Licensed CC0.

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