Gene

Regulatory network between transcription factor, oncogene, histone modification and  scgf

 










































 GeneAssist Pathway Atlas provides scgf gene-related interactive pathway maps.
 ESCAPE (Embryonic Stem Cells Atlas of Pluripotency Evidence) presents gene-protein interaction database in
 ES cells.

(1) NF-κB　　　　　　　　　　　　　　　　　　　　　　　　　　　　　
  Scgf gene is up-regulated when NF-κB is inactivated in HeLa cells by adding tetracyclin (109), HeLa^{tTA/FLAG-1
κBMut} cells by depriving doxycyclin (110) or SHEP-1 neuroblastoma cells by treating with I-κBαM (179). The
 correlation of NF-κB inactivation and scgf  gene up-regulation is compatible with that of umbilical cord blood and
 bone marrow CD34⁺ cells. NF-κB and scgf gene is up- and down-regulated, respectively, in umbilical cord blood
 CD34⁺ cells as compared with bone marrow CD34⁺ cells (38).
  Scgf gene expression is highly down-regulated in the RelA^-/-  (a component of NF-κB) hES cell-derived MSCs,  
 and they exhibit defective self-renewal ability (592). Knockdown of wild type hMSCs with scgf shRNA abrogates  
 their proliferative potential, indicating that scgf is a mandatory driver for MSC proliferation.
  Scgf gene expression is highly up-regulated in t(4;14)-positive myeloma cells with MMSET overexpression.  
 Knockdown of t(4;14)-positive KMS-26 and NCI-H929 myeloma cells with scgf siRNA down-regulates expression of
 NF-κB, a target for MMSET, and decreases cell viability by 60% associated with increased annexin V-positive
 apoptotic cells (536).
  NF-κB activation as seen in API2-MALT1⁺ gastric MALT lymphoma is linked to down-regulation of scgf gene at
 chromosome 19q13.2-q13.4 (232).
(2) Nrf-2, Nrf1　　　　　　　　　　　　　　　　　　　　　　　　
　　Nrf-2 (nuclear E2-factor related factor) exhibits cancer chemopreventive effect by binding to antioxidant
 response element within the promoter area of detoxic enzyme. Scgf  gene is Nrf-2-dependently up-regulated, i.e.
 not in Nrf-2^-/- but in Nrf-2^+/+ mice in the liver when Nrf-2 is activated with sulforaphane (112) or
 phenethylisothiocyanate (113). Scgf gene is Nrf-2-dependently down-regulated when Nrf-2 is inactivated with
 endoplasmic reticulum stress inducer tunicamycin (114).　　
   Nrf1
  Scgf is a target gene for Nrf1 (nuclear respiratory factor 1) and also associated with estrogens and estrogen  
 endocrine disruptors such as bisphenol-A, phthalates and cadmium (541).
(3) Runx2
  Runx2 functions in bone formation associated with neurogenesis and hematopoiesis. Scgf gene is under control of
 runx2 since down-regulated in the bones of runx2^-/- mice as compared with runx2^+/+ mice (40, 44).
(4) Myc　　　　　　　　　　　　　　　　　　　　　　　
   Ingenuity pathway analysis on doxycyclin-controlled transgenic mice^{Eμsrα-tTAmyc} discloses scgf and integrinα
 M chain gene regulated by myc (115).
  Scgf promoter is a target bound by Myc-related factors and histone modification in ES, iPS and cancer cells (274).
   Histone modifications of scgf gene are listed based on ChIP-chip/seq studies in ES cells, iPS cells, MEFs, neural
 progenitor cells and whole brain (ESCAPE; Embryonic Stem Cells Atlas of Pluripotency Evidence).
   c-Myc and H3K4me3 binds to scgf gene promoter in murine epidermal keratinocytes (353).
   H3K4me3 binds to scgf gene specifically in precursor T cell leukemia cell lines derived from NUP98-PHF23  
 transgenic mice (453).
   H3K27ac and H3K4me3 bind to scgf in both rat oligodendrocyte precursor cells and differentiated  
 oligodendrocytes, while H3K9me3 binds to scgf in the former cells but not in the latter cells (461).

Dmap1 (NuA4)

E2F1

E2F4

c-Myc

Max

n-Myc

Zfx

Rex1

Tip60

Cnot3

Trim28

AcH3

AcH4

H3K4me3

H3K27ac

-

+

+

+

+

+

-

-

-

-

-

+

-

+

+

   +: bound, -: unbound
(5) Stem cell-related factors
  None of stem cell-related factors bind to scgf promoter in ES, iPS and cancer cells (274,290).

Smad1	Stat3	Klf4	Oct4(Pou5f1)	Nanog	Sox2	Nac1	Zfp281	Dax1
-	-	-	-	-	-	-	-	-

   -: unbound
   ChIP-chip/seq analyses demonstrate interaction between scgf gene and transcription factors in mES cells,
 including E2F4, Esrrb, Max, Med1, Med12, Myc, Nipbl, Rcor3, Rest, Rnf2, Smc1A, Smc3, Sox2, Suz12 and Tcf3
 (ESCAPE; Embryonic Stem Cells Atlas of Pluripotency Evidence).
   Knockdown or overexpression experiment identifies scgf-regulatory transcription factors in ES cells, including
 Ascl2, Klf4, Nr5A2, Smc1A , Sox2 and Tcf3 (ESCAPE; Embryonic Stem Cells Atlas of Pluripotency Evidence).
   Knockdown of scgf gene expression with scgf siRNA does not significantly down-regulate POU5F1 gene promoter
 in human H1 ES cells (285).
   Oct4-transduced normal mammary epithelial cells up-regulate scgf gene expression and acquire cancer stem cell  
 nature (345).
(6) TGF-β/Activin/Nodal-Smad2,3-Smad4
   BMP-Smad1,5,8-Smad4
   Smad2,4 but not Smad1,5 bind to scgf promoter [chr7:40483523-40483701(178bp)] in mouse ES cells (290, 291).  
 Activin up-regulates scgf gene expression in mouse ES cells (291).
(7) E2F1
  Scgf gene expression is under control of transcription factor E2F1, i.e. scgf gene is down-regulated 20-fold in the
 pancreatic islet cells of E2F1^-/- mouse as compared with wild type controls (217). E2F1 binds to scgf promoter in
 ES, iPS and cancer cells (274).
(8) p53　　　　
　　Scgf gene is significantly down-regulated in mutant p53Q373-expressed H1299 and A549 lung cancer cells as
 compared with non-mutant p53-expressed cells (116). p53Q373 suppresses transcription of anti-apoptotic
 promoter more efficiently than p53 to induce apoptosis, which is accelerated by down-regulation of scgf  gene.
(9) PU.1
   Ets transcription factor PU.1 is encoded by Sfpi1 gene in mice. PU.1 activates myeloid/B-cell lineage-specific
 genes, but represses T/NK-cell lineage-specific genes. Scgf gene expression is 2.5-fold up-regulated in the IL-3-
 dependent myeloid cell line derived from fetal liver cells of Sfpi1^Blac/Blac mice (2% PU.1 of the wild type mice at
 protein level) relative to Sfpi1^-/- cells, but returns to the baseline of Sfpi1^-/- cells in Sfpi1^BN/BN cells (20% PU.1)
 (224). The PU.1 dose-independent findings indicate that scgf gene expression is not subject to PU.1
(10) Tcf3, Tbx3
   Scgf gene expression is insignificantly affected in the Tcf3 or Tbx3 RNAi knockdown ES cells (233).
(11) Stat3, Stat5
   Stat3 but not stat5 regulates scgf gene expression in CWR22Rv1 human prostate cancer cells (245). Stat3 does
 not bind to scgf promoter in ES, iPS and cancer cells (274).
(12) POU4F1
   Scgf gene expression is up-regulated in t(8;21)-psitiveAML cells independent on POU4F1 gene dysregulation (247)
(13) ATAD2
   Scgf gene expression is significantly up-regulated when ATAD2 gene is knocked down by treating human lung
 adenocarcinoma cell line, A549, with an ATAD2-targeting siRNA (261).
(14) Polycomb
   Scgf promoter is a target for Polycomb-related factors and histone modification in ES, iPS and cancer cells (274).
   Histone modifications of scgf gene are listed based on ChIP-chip/seq studies in ES cells, iPS cells, MEFs, neural
 progenitor cells and whole brain (ESCAPE; Embryonic Stem Cells Atlas of Pluripotency Evidence).
   Scgf gene expression is little affected in undifferentiated and differentiated mouse ES cells lacking H3K4 lysine-
 specific demethylase 5A (Kdm5a) compared to Kdm5a^+/+ cells (391). Kdm2b and Ezh2 but not Ring1b target scgf  
 promoter CpG island in the mouse ES cells (412). Scgf is a target gene for Ezh2 and ubiquitinated H2AK119  
 in DU145 prostate cancer cells (445).
   Scgf is a target gene for Cbx7 but not for Cbx8 in the hematopoietic stem cells (411).
   Scgf gene expression is significantly down-regulated in the cumulus cells from older women (>40yr old) relative to younger women (<35yr old). Suz12 is a transcription factor for scgf  (532).

Suz12

Eed

Phc1

Rnf2

Ezh1

Ezh2

H3K27me3

uH2A

CTCF

Cbx7

Cbx8

Kdm2b

Kdm5a

Ring1b

+

+

-

-

+

+

-

+

-

+

-

+

+

-

   +: bound, -: unbound
(15) HOXB4
   Scgf gene expression is up-regulated in HOXB4-overexpressed c-kit⁺Lin^-Sca-1⁺ subpopulation of murine EML    
 primitive hematopoietic cells relative to GFP-expressing vector only EML cells, indicating that scgf  is one of the
 "stemness"-specific target genes of HOXB4 (315).
(16) Notch1
   When Notch1 signaling is inhibited in rat aortic valve interstitial cells by Γ-secretase inhibitor, scgf gene  
 expression is down-regulated (347).
(17) Wnt3a, Wnt5a
   Transduction of mouse BM stromal OP9 cells with wnt3a alters their mesenchymal stem cell characteristics into
  that of osteoblasts, and extremely up-regulates scgf gene expression in addition to decorin, fibromodulin and
  tenascin (361). Wnt5a gene is specifically up-regulated in the osteoblasts differentiated from MSCs. Scgf gene is
  down-regulated in the calvaria of wnt5a^-/- mice as compared with that of wnt5a^+/+ mice (43).
(18) Per1
   Circadian clock Per1 gene maintains murine CD34⁺Α6 integrin^brightPer1-venus^bright hair follicle epidermal        
 stem cells dormant, where scgf gene expression is up-regulated relative to the Per1-venus^dim stem cells (352).
(19) Lamin-B1
   Lamin-B1 binding to scgf  gene promoter is significantly up-regulated in murine trophectoderm cells compared      
 with ES cells (357).
(20) Histone deacetylase (HDAC)
   Trichostatin A, a potent HDAC inhibitor, up-regulates scgf gene expression in F9 mouse embryonal carcinoma cells
 (275) and BE(2)-C neuroblastoma cells (283).
(21) Etv6, Pax6
   Scgf gene is bound by Etv6 but not Pax6 in the mouse NSEB5-2C neural progenitor cells even after iPSC  
 induction (416).
(22) EWS
   Scgf gene is usually up-regulated in Ewing family tumor (one of small round blue tumor associated with EWS/FLI1
 translocation is estimated to be originated in tumorigenesis between neural crest from neural ectoderm and
 mesenchymal-vascular endothelial lineage) (154,249).
   EWS-FLI1 binds to the (GGAA)n microsatellite (Chr19:55933752-55934360) of scgf gene promoter, and activates
 transcription (278).
(23) Cyclin D1
   Cyclin D1 binds to scgf promoter (Chr7:40478877-40478922) in the retina from cyclin D1-knockin mouse, possibly
 regulating scgf gene expression, but retinas from cyclin D1-knockout (Ccnd1^-/-) mouse show no significant change
 in scgf gene expression as compared to wild type controls (281).
(24) Argonaute
   Argonaute (AGO) 2 binds to scgf gene promoter in RAS^V12-induced senescent primary WI38 fibroblasts, but not  
 in presenescent control cells (364).
(25) MMSET/WHSC1
   Myeloma cells with t(4;14)(p16.3;q32) overexpress gene network between MMSET/WHSC1, FGFR3 and scgf  (365).
(26) Bre1, histone H2B ubiquitin ligase
   Deletion of histone H2B ubiquitin ligase Bre1 by RNAi down-regulates scgf gene expression in mouse fibrosarcoma
 RIF-1 cells (367).
(27) CREB
   Scgf gene expression is down-regulated in the CREB-overexpressed nucleus accumbens shell of socially isolated  
  adult rats (390).
(28) BRIP1
   Scgf gene expression is up-regulated in normal mammary epithelial MCF-10A cells when BRCA1-interacting  
 helicase BRIP1 is knocked down (426).
(29) DNA methyltransferase (Dnmt1, Dnmt3a, Dnmt3b)/DNA methylation
   Differentiation of epidermal progenitor cells to keratinocytes down-regulates DNA methyltransferase 1 (Dnmt1)
 gene expression, along which scgf gene is somewhat up-regulated and loses methylation (280). However Dnmt1
 knockdown with Dnmt1 shRNA little affects scgf gene expression.
   Scgf gene expression is down-regulated in Dnmt3a-knockout (KO) mouse HSCs but up-regulated in Dnmt3a/
 Dnmt3b-double KO HSCs, while most genes show no dissociated regulation between Dnmt3a-KO and Dnmt3a/
 Dnmt3b-double KO HSCs (471). Scgf gene expression is up-regulated in the ITGα6⁺ epidermal tumor cells from
 conditional Dnmt3a-KO mice treated with DMBA and TPA (560).
   Methylome analysis on hematopoietic progenitors indicates that CpG sites in the scgf promoter are differentially  
 methylated between Lin^-Il7ra^-c-Kit⁺Sca-1⁺CD34⁺Flt3⁺ multipotent progenitors (MPP) and Lin^-CD27⁺Flt3⁺Il7ra⁺
 Ly6D^- common lymphoid progenitors (CLP) (MPP>CLP), between CLP and Lin^-CD4^-CD8^-c-Kit⁺CD44⁺CD25^-
 thymocyte progenitors (DN1) (DN1>CLP), and between DN1 and Lin^-CD4^-CD8^-c-Kit⁺CD44⁺CD25⁺ thymocyte
 progenitors (DN2) (DN1>DN2) (284).
   CpG sites of scgf gene promoter are differentially hypomethylated in the pediatric ALL cells at relapse as    
 compared to the matched cells at diagnosis (344). Scgf gene is differentially expressed and methylated in pediatric  
 ALL cells compared to normal CD19⁺ cells (617). Prenatal maternal exposure to low levels of lead induces  
 hypomethylation of CpG site cg10773601 upstream to scgf gene in the newborn umbilical cord blood cells (564).
   Dcitabine significantly demethylates scgf gene promoter in MLL5⁺ mouse BM cells relative to MLL5^- cells (470).
   Scgf gene in peripheral blood mononuclear cells from healthy 1 year old child shows a significant gain in DNA
 methylation relative to cord blood mononuclear cells from the same child (182).
   Scgf gene is hypermethylated in the ovary from neonatal rats exposed to high dose of pesticide methoxychrol  
 during fetal and neonatal stages (406).
   Scgf is one of the genes within partially methylated domains of genome DNA from human placenta (415).

Regulation of  scgf gene expression
Up	No	Down
AcH3 Bre1 Cbx7 c-Myc E2F1 E2F4 Eed EWS Ezh1 H3K4me3 HOXB4 Max n-Myc Notch1 Nrf-2 Oct4 (Pou5f1) p53 Per1 Runx2 Suz12 Wnt3a Wnt5a	AcH4 Cbx8 Cnot3 CTCF Cyclin D1 Dax1 Dmap1 (NuA4) Etv6 Ezh2 H3K27me3 Kdm2b Kdm5a Klf4 Lhx2 Nac1 Nanog Oct4 (Pou5f1) Pax6 Phc1 Pou4f1 PU.1 Ring1b Rex1 Rnf2 Smad1 Smad5 Sox2 Stat3 Tbx3 Tcf3 Tip60 Trim28 Zfx Zpf281	ATAD2 Cbx7 CREB HDAC Lamin-B1 NF-κB BRIP1