TABLE 3.

Significantly dysregulated upstream regulators and constituent downstream genes in powdered chow-exposed fetal brain.

Upstream regulator	Entrez gene name	Putative function	Molecule type	Predicted activation state	Bias-corrected Z-score	Target molecules in dataset
EP400	E1A binding protein p400	Cell cycle regulation; chromatin organization; histone H2A acetylation; histone H4 acetylation	other	Activated	2.063	CDCA3, CENPF, FBXO5, INCENP, MCM3, SUV39H2 (direction of regulation predicts EP400 activation in 6/6)
ISL1	ISL LIM homeobox 1	Encodes a member of the LIM/homeodomain family of transcription factors. The encoded protein may play an important role in regulating insulin gene expression.	Transcription regulator	Activated	2.009	CRABP1, NPY, NXPH4, OLIG1 (direction of expression predicts ISL1 activation in 4/4)
PTGER2	Prostaglandin E receptor 2	Encodes a receptor for prostaglandin E2, a metabolite of arachidonic acid. Within the brain, PGE2 receptors are involved in the regulation of synaptic activity and plasticity, in brain maturation, and are key mediators of the brain’s response to inflammation. This gene has been implicated in negative regulation of the apoptotic process	G-protein coupled receptor	Activated	3.623	ARFGEF1, CENPE, CENPF, CEP55, CKAP2L, ECT2, KIF11, KIF15, KIF20A, KIF2C, MELK, MKI67, NUF2, PRC1, STIL, TPX2, TTK (direction of expression predicts PTGER2 activation in 17/17)
POU4F1	POU class 4 homeobox 1	Encodes a member of the POU-IV class of neural transcription factors. Implicated in sensory nervous system development, axonogenesis, and negative regulation of central nervous system apoptosis	Transcription regulator	Activated	2.013	CHRNA3, CRABP1, NECAB2, NPY, NXPH4, OLIG1, RTN4RL2, SSTR4 (direction of expression predicts activation of POU4F1 in 4/8)
CLOCK	Clock circadian regulator	Encodes a protein that is a key regulator of circadian rhythms. Polymorphisms in this gene are associated with obesity and metabolic syndrome in certain populations.	Transcription regulator	Activated	2.248	CADM2, CLIP1, CTGF, GCC2, GTF2E1, ITM2C, LYPD6, OPN3, OSTM1, PCGF5, PIP4K2C, QSER1, THUMPD1, TIMP4 (direction of expression predicts CLOCK activation in 11/14 genes)
BDNF	Brain derived neurotrophic factor	Encodes a member of the nerve growth factor family of proteins. Inhibition of expression is associated with cognitive deficits and neurogenerative disorders such as Alzheimer’s, Parkinson’s, and Huntington’s disease.	Growth factor	Inhibited	–2.781	ALDH7A1, ANXA5, Cdkn1c, DNAJC21, DRD2, EGR1, HSD17B4, HSPA4L mir-10, mir-154, NCDN, NPY, PCDH8, RGS4, SCCPDH, SFR1, TMED2, Tmsb4x, VAMP2, VGF (direction of expression predicts BDNF inhibition in 12/20)
IL33	Interleukin 33	Encodes a cytokine that binds to the IL1RL1/ST2 receptor. Encoded protein is involved in the maturation of Th2 cells and the activation of mast cells, basophils, eosinophils and natural killer cells. Gene has been implicated in microglial activation and the brain’s innate immune response.	cytokine	Inhibited	–3.102	ACAT1, ARRB1, CCL3L3, ENO2, HACD3, NFKBIB, PRPF4B, RAI14, RAMP3, RASGRP1 (direction of expression predicts IL33 inhibition in 8/12)
BNIP3L	BCL2 interacting protein 3 like	Encodes a protein that belongs to the pro-apoptotic subfamily within the Bcl-2 family of proteins. The encoded protein directly targets mitochondria and causes apoptotic changes, including loss of membrane potential and the release of cytochrome c.	Other	Inhibited	–2.94	CCND3, CENPE, CENPF, CKAP2, CST3, GADD45A, GPSM2, KIF11, NT5C3A, NUF2, PRIM1, RAD54L, TOP2A (direction of expression predicts inhibition in 12/13)
KLF3	Kruppel like factor 3	Transcription factor that is a key regulator of adipogenesis and B cell development. KLF3 serves as a key regulator of neuronal development, and dysregulation of regulators in the KLF famiuly has been linked to has been linked to various neurological disorders. KLFs may play a key role in brain vasoprotection and neuroprotection in response to ischemic or hypoxic stimuli.	Transcription regulator	Inhibited	–2.241	AGGF1, ANXA5, CEP63, CHCHD10, CSNK1G3, EEF1AKMT1, EPRS, HNRNPH1, HYPK, IGF2BP3 (direction of expression predicts inhibition in 25/35)
F2	Coagulation Factor II; Thrombin	Coagulation factor II is proteolytically cleaved to form thrombin in the first step of the coagulation cascade which ultimately results in the stemming of blood loss. F2 also plays a role in maintaining vascular integrity during development and postnatal life.	Peptidase	Inhibited	–2.821	B4GALT1, BIRC2, CTGF, DOK5, EGR1, F3, PPIF, RAC1, RHOJ, SLC2A6 (direction of expression predicts inhibition in 10/12)
C5	Complement 5	Encodes a component of the complement system, part of the innate immune system that plays an important role in inflammation, host homeostasis, and host defense against pathogens	Cytokine	Inhibited	–2.101	CCL3L3, EFNB2, EGR1, F3, PLK3 (direction of expression predicts inhibition in 4/5)