A Novel Divergent Gene Transcription Paradigm—the Decisive, Brain-Specific, Neural |-Srgap2–Fam72a-| Master Gene Paradigm

  • Nguyen Thi Thanh Ho
  • Arne Kutzner
  • Klaus HeeseEmail author


Brain development and repair largely depend on neural stem cells (NSCs). Here, we suggest that two genes, i.e., Srgap2 (SLIT-ROBO Rho GTPase–activating protein 2) and Fam72a (family with sequence similarity to 72, member A), constitute a single, NSC-specific, |-Srgap2–Fam72a-| master gene pair co-existing in reciprocal functional dependency. This gene pair has a dual, commonly used, intergenic region (IGR) promotor, which is a prerequisite in controlling human brain plasticity. We applied fluorescence cellular microscopy and fluorescence-activated cell sorting (FACS) to assess rat |-Srgap2–Fam72a-| master gene IGR promotor activity upon stimulation with two contrary growth factors: nerve growth factor (Ngf, a differentiation growth factor) and epidermal growth factor (Egf, a mitotic growth factor). We found that Ngf and Egf acted on the same IGR gene promotor element of the |-Srgap2–Fam72a-| master gene to mediate cell differentiation and proliferation, respectively. Ngf mediated Srgap2 expression and neuronal survival and differentiation while Egf activated Fam72a transcription and cell proliferation. Our data provide new insights into the specific regulation of the |-Srgap2–Fam72a-| master gene with its dual IGR promotor that controls two reverse-oriented functional-dependent genes located on opposite DNA strands. This structure represents a novel paradigm for controlling transcription of divergent genes in regulating NSC gene expression. This paradigm may allow for novel therapeutic approaches to restore or improve higher cognitive functions and cure cancers.


Brain Cell cycle Differentiation Divergent transcription Gene promotor Proliferation 



AK strain transforming, AKT serine/threonine kinase


Analysis of variance


Activating transcription factor 1


BCL2-associated agonist of cell death


BCL2-antagonist/killer 1


BCL2-associated X


B cell lymphoma 2


Bcl2-like 1


BH3-interacting domain death agonist


B rapidly accelerated fibrosarcoma (B-Raf) proto-oncogene, serine/threonine kinase


Binding site


Bovine serum albumin




Cyclin A/B/D/E


Cyclin-dependent kinase


Cyclin-dependent kinase inhibitor 1A






Central nervous system


cAMP-responsive element-binding protein 1


Cytochrome c, somatic




Differential interference contrast


Dulbecco’s modified Eagle’s medium




E2 transcription factor


Ethylenediaminetetraacetic acid


Epidermal growth factor


Epidermal growth factor receptor


Fluorescence-activated cell sorting


Family with sequence similarity 72, member A


Fetal bovine serum


Finkel-Biskis-Jinkins (FBJ) murine osteosarcoma (Fos) proto-oncogene, activator protein 1 (AP-1) transcription factor subunit


Green fluorescent protein


Histone deacetylase 1


4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid


Horse serum




Intergenic region


Internal ribosome entry site 2


Korean cell line bank


Lysine methyltransferase 5B/C


Mitogen-activated protein kinase kinase


Mitogen-activated protein kinase


Myeloid cell leukemia 1, BCL2 family apoptosis regulator


Murine double minute 2 proto-oncogene


Mitochondrial outer membrane permeabilization


Metallothionein 1


Myelocytomatosis viral oncogene


National Center for Biotechnology Information


Nucleosome-depleted region


Non-essential amino acids


Nerve growth factor


Neural stem cell


Neurotrophic receptor tyrosine kinase 1




Penicillin, streptomycin


Plasmid DNA


Phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit gamma


Promoter upstream transcript


Ras-related protein 1


Rat sarcoma (RAS) proto-oncogene, GTPase


Retinoblastoma (RB) transcriptional corepressor


Red fluorescent protein


Standard error of the mean


SLIT-ROBO Rho GTPase–activating protein 2


Suppressor of variegation 3-9 homolog 1


Transcription factor


Transcription factor–binding sites


Transcription factor dimerization partner 1 (Dp-1)


Tumor protein 53







We thank Hanyang University for providing a scholarship to Ms. N. T. T. H.

Funding Information

This study was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), which was funded by the Ministry of Education (2015R1D1A1A01057243).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Graduate School of Biomedical Science and EngineeringHanyang UniversitySeoulRepublic of Korea
  2. 2.Department of Information Systems, College of EngineeringHanyang UniversitySeoulRepublic of Korea

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