Blood cells are derived from a common set of hematopoietic stem cells, which differentiate into more specific progenitors of the myeloid and lymphoid lineages, ultimately leading to differentiated cells. This developmental process is controlled by a complex regulatory network involving cytokines and their receptors, transcription factors, and chromatin remodelers. Using public data and data from our own molecular genetic experiments (quantitative PCR, Western blot, EMSA) or genome-wide assays (RNA-sequencing, ChIP-sequencing), we have assembled a comprehensive regulatory network encompassing the main transcription factors and signaling components involved in myeloid and lymphoid development. Focusing on B-cell and macrophage development, we defined a qualitative dynamical model recapitulating cytokine-induced differentiation of common progenitors, the effect of various reported gene knockdowns, and the reprogramming of pre-B cells into macrophages induced by the ectopic expression of specific transcription factors. The resulting network model can be used as a template for the integration of new hematopoietic differentiation and transdifferentiation data to foster our understanding of lymphoid/myeloid cell-fate decisions. Pribil Erica epribil8@gmail.com University of Nebraska-Lincoln 2017-06-16T14:30:46Z 2017-07-25T20:46:31Z

Uniprot ID: P09603

Protein: Macrophage colony-stimulating factor 1

Gene: CSF1

 2017-06-21T11:09:19Z

Uniprot ID: P13232

Protein: Interleukin-7

Gene: IL7

 2017-06-21T10:00:03Z

Uniprot ID: P15923

Protein: Transcription factor E2-alpha

Gene: TCF3

 2017-06-21T11:45:35Z

Uniprot ID: P36888

Protein: Receptor-type tyrosine-protein kinase FLT3

Gene: FLT3

 2017-06-21T10:05:35Z

Uniprot ID: Q02363

Protein: DNA-binding protein inhibitor ID-2

Gene: ID2

 2017-06-21T12:00:48Z

Uniprot ID: P16871

Protein: Interleukin-7 receptor subunit alpha

Gene: IL7R

Activated from of IL7R

 2017-06-21T11:54:37Z

Uniprot ID: P17676

Protein Name: CCAAT/enhancer-binding protein beta

Gene: CEBPB

 2017-06-21T11:58:52Z

Uniprot ID: Q02548

Protein: Paired box protein Pax-5

Gene: PAX5

 2017-06-21T12:00:13Z

Uniprot ID: Q9UH73

Protein: Transcription factor COE1

Gene: EBF1

 2017-06-21T11:58:52Z

Uniprot ID: P15391

Protein: B-lymphocyte antigen CD19

Gene: CD19

 2017-06-21T12:01:57Z

Uniprot ID: P17947

Protein: Transcription factor PU.1

Gene: SPI1

 2017-06-22T08:13:58Z

Uniprot ID: Q02548

Protein: Paired box protein Pax-5

Gene: PAX5

 2017-06-21T12:01:57Z

Uniprot ID: P11215

Protein: Integrin alpha-M

Gene: ITGAM

Activated from of the Mac1 gene

 2017-06-21T10:50:25Z

Uniprot ID: P15391

Protein: B-lymphocyte antigen CD19

Gene: CD19

Refers to the activated form of the gene.

 2017-06-21T12:01:57Z

Uniprot ID: P49715

Protein Name: CCAAT/enhancer-binding protein alpha

Gene Name: CEBPA

 2017-06-21T11:07:06Z

Uniprot ID: Q06413

Protein: Myocyte-specific enhancer factor 2C

Gene: MEF2C

 2017-06-21T11:36:26Z

Uniprot ID: Q12778

Protein: Forkhead box protein O1

Gene: FOXO1

 2017-06-22T08:13:58Z

Uniprot ID: P14921

Protein: Protein C-ets-1

Gene: ETS1

 2017-06-21T11:53:10Z

Uniprot ID: Q13422

Protein: DNA-binding protein Ikaros

Gene: IKZF1

 2017-06-22T08:13:58Z

Uniprot ID: P07333

Protein: Macrophage colony-stimulating factor 1 receptor

Gene: CSF1R

 2017-06-21T10:06:24Z

Uniprot ID: Q99684

Protein: Zinc finger protein Gfi-1

Gene: GFI1

 2017-06-21T11:30:27Z

Uniprot ID: Q9UH73

Protein: Transcription factor COE1

Gene: EBF1

 2017-06-21T11:51:23Z

Uniprot ID: Q02548

Protein: Paired box protein Pax-5

Gene: PAX5

Activated form of Pax5 gene

 2017-06-21T12:00:48Z

Uniprot ID: P07333

Protein: Macrophage colony-stimulating factor 1 receptor

Gene: CSF1R

Activated form of CSF1R

 2017-06-22T10:33:27Z

Uniprot ID: P17947

Protein: Transcription factor PU.1

Gene: SPI1

 2017-06-21T11:22:47Z

Uniprot ID: Q12778

Protein: Forkhead box protein O1

Gene: FOXO1

 2017-06-21T11:48:15Z

Uniprot ID: Q01196

Protein: Runt-related transcription factor 1

Gene: RUNX1

 2017-06-22T08:13:58Z

Uniprot ID: P15923

Protein: Transcription factor E2-alpha

Gene: TCF3

 2017-06-21T11:46:27Z

Uniprot ID: P11215

Protein: Integrin alpha-M

Gene: ITGAM

 2017-06-21T13:37:12Z

Uniprot ID: P49715

Protein Name: CCAAT/enhancer-binding protein alpha

Gene Name: CEBPA

Refers to the activated from of the gene.

 2017-06-21T12:01:57Z

Uniprot ID: P18146

Protein: Early growth response protein 1

Gene: EGR1

 2017-06-21T11:30:27Z

Uniprot ID: P16871

Protein: Interleukin-7 receptor subunit alpha

Gene: IL7R

 2017-06-21T11:42:55Z

Uniprot ID: P15923

Protein: Transcription factor E2-alpha

Gene: TCF3

 2017-06-21T11:51:23Z

Ikzf1, Ebf1 and Pax5_protein_active activate E2A_gene.

Ikzf1 and Spi1 activates E2A_gene.

It is predicted that Ikzf1 regulates E2A_gene from ChIP-seq meta analysis data.

Spi1 activates the E2A_gene through binding.

Ebf1 acts in a positive feedback loop to regulate the E2A_gene.

The Pax5 protein binds with ebf1 to activates the E2A_gene.

 S_17 1 S_9 1 S_17 1 S_7 1 S_10 1

Spi1 and Ikzf1 activate Flt3, unless Pax5_protein_active.

Spi1 activates Flt3 via phosphorylation.

Ikzf1 activates Flt3 via binding.

Increased Pax5_protein_active activity is associated with decreased Flt3 activity.

 S_9 1 S_10 1 S_17 1

Cebpb, Cebpa and Spi1 activate, unless Ebf1 and Gfi1 are active.

Spi1 and Id2 appear to interact together.

Cebpa activates Id2 via ligand binding.

Cebpb activates Id2 via ligand binding.

Increased Ebf1 activity is associated with decreased Id2 activity.

Gfi1 inhibits Id2 by binding to 3 conserved regions in the promoter.

 S_5 1 S_7 1 S_19 1 S_9 1 S_30 1

IL7 and IL7r activate IL7r_activated.

IL7r_activated refers to the active from of IL7r.

IL7 activates IL7r_activated through binding.

 S_25 1 S_32 1

Spi1_2 and Cebpa or Cebpb activate Cebpb.

Cebpa and Cebpb are associated with interactions with eachother.

Cebp factors appear to activates eachother.

Spi1 activates Cebpb through binding.

 S_24 1 S_30 1 S_5 1

Ebf1 activates Pax5_gene, unless Cebpa or Cebpb are active.

Increased Cebpa activity is associated with decreased Pax5_gene activity.

Ebf1 activates Pax5_gene by binding.

Increased Cebpb acitivity is associated with decreased Pax5_gene activity.

 S_7 1 S_30 1 S_5 1

Ebf1_gene activates Ebf1.

Ebf1 refers to the activated part of the ebf1 gene.

 S_21 1

Pax5_protein_active activates the Cd19_gene, unless Cebpa is active.

Cebpa binding inhibits CD19 activity.

Increased Pax5 activity is associated with increased CD19 activity.

 S_10 1 S_30 1

Spi1 and Runx1 and (Gfi1 or not Cepbb and not Csf1r_activated or not Cebpa and not Csf1r_activated) activate Spi1.

Foxo1, Ebf1 and Ikzf1 activate Spi1, unless Runx1 or Spi1 are active.

Spi1, Runx1, Ikzf1 and not Foxo1 activate Spi1.

Spi1 has been known to regulate itself by binding.

Data from ChIP analysis and functional variances imply that Ikzf1 has the ability to inhibit or active Spi1/ Spi1_2 via different cis elements of the PU.1 gene.

Increased Runx1 activity is associated with increased Spi1 activity.

Runx1 has been know to inhibit certain corespressors that affect Spi1 activity.

Increased Cebpa activity is associated with decreased Spi1 activity.

Increased Ebf1 activity is associated with increased Spi1 activity.

Increased Csf1r_activated activity is associated with decreased Spi1 activity.

It is predicted that Cebpb regulates Spi1 from ChIP-seq meta- analysis data.

It is predicted that Foxo1 regulates Spi1 from ChIP-seq meta- analysis data.

Gfi1 has been known to activates Spi1 in some cases.

 S_9 1 S_27 1 S_15 1 S_17 1 S_9 1 S_27 1 S_19 1 S_23 1 S_5 1 S_30 1 S_23 1 S_15 1 S_17 1 S_7 1 S_9 1 S_27 1

Pax5 activates Pax5_protein_active, unless Id2 is active.

By repressing the gene expression of the activation-induced cytidine deaminase, Id2 inhibits Pax5_protein_active activity.

Pax5_protein_active refers to the activated protein made by Pax5.

 S_22 1 S_3 1

Mac1_gene activates Mac1.

Mac1 refers to the activated part of the Mac1 gene.

 S_29 1

CD19_gene activates Cd19.

CD19 refers to the actived from of the CD19_gene.

 S_8 1

Spi1 and Runx1 activates Cebpa_gene, unless Foxo1 is active.

Spi1 activates Cebpa_gene through binding.

Runx1 activates Cebpa_gene via phosphorylation reactions.

It is predicted that Foxo1 regulates cebpa_gene from ChIP-seq meta-analysis data.

Acetylation of foxo1 have been knwon to inhibit cebpa activity.

 S_9 1 S_27 1 S_15 1

Spi1 activates Mef2c, unless Cebpa or Cebpb are active.

Increased Spi1 activity is associated with increased Mef2c activity.

Increased Cebpa activity is associated with decreased Mef2c activity.

Increased Cebpb activity is associated with decreased Mef2c activity.

 S_9 1 S_30 1 S_5 1

E2A activates Foxo1, unless Cebpa is active.

E2A activates Foxo1 through binding.

Cebpa inhibits Foxo1 through an unknown mechanism.

 S_28 1

E2A_protein_active activates Ets1.

E2A_protein_active activates Ets1 through binding.

 S_33 1

Mef2c or Pax5_protein_active activate Ikzf1.

Mef2c activates Ikzf1 through binding.

Pax5_protein_active and Ikzf1 have been known to interact together.

 S_14 1 S_10 1

Spi1 activates Csf1r unless Pax5_protein_active.

Spi1 activates Csflr through binding.

The pax5 protein prevents Csf1r activity by interfering with the mechanism of myeloid transcription factors.

 S_9 1 S_10 1

Pax5_protein_active activates Gfi1.

Ikzf1 or Cebpa activate Gfi1, unless Egr1 is active.

Ikzf1 activates Gfi1 through binding.

Egr1 inhibits Gfi1 through an unknown mechanism.

Cebpa activates Gfi1 by binding in the Gfi-1 5′ flanking region.

Pax5_protein_active activates Gfi1 through binding.

 S_10 1 S_17 1 S_31 1 S_30 1 S_31 1

E2A_protein_active along iwth Ebf1, Ets1, Foxo1 and Pax5_protein_active activate Ebf1_gene, unless Cebpa or Cebpb are active.

Spi1 helps regulate the proximal promoter of Ebf1_gene.

Increased Runx1 activity is associated with increased Ebf1_gene activity.

Cebpa have been known to inhibit Ebf1_gene.

Ebf1 refers to the activated part of the ebf1 gene.

Foxo1 along with E2A_protein_active, Ebf1 and Pax5_protein_active encourage B-cell development through positive feedback.

Cebpb have been known to inhibit Ebf1_gene.

Ets1 helps regulate the proximal promoter of the Ebf1_gene.

Foxo1 along with E2A_protein_active, Ebf1 and Pax5_protein_active encourage B-cell development through positive feedback.

IL7r_activated signaling helps activate the distal promoter of the Ebf1_gene.

E2A_proteiin_active activates Ebf1_gene through binding.

Foxo1 along with E2A_protein_active, Ebf1 and Pax5_protein_active encourage B-cell development through positive feedback.

Pax5_protein_active helps regulate the proximal promoter of the Ebf1_gene.

Foxo1 along with E2A_protein_active, Ebf1 and Pax5_protein_active encourage B-cell development through positive feedback.

 S_33 1 S_7 1 S_16 1 S_15 1 S_10 1 S_30 1 S_5 1 S_33 1 S_9 1 S_27 1 S_16 1 S_15 1 S_4 1 S_30 1 S_5 1

Pax5_gene activates Pax5.

Pax5 refers to the activated form of the Pax5 gene.

 S_6 1

Csf1r and Csf1 activates Csf1r_activated.

Csf1r_activated refers to the activated from of Csf1r.

Csf1 activates Csf1r_activated through ligand binding.

 S_18 1 S_20 1

Runx1, Cs1lr_activated, Spi1 and Cebpa or Cebpb activate Spi1_2.

Runx1 and Spi1 activate Spi1_2, unless Gfi1 or Foxo1 and Ikzf1 are active.

Spi1_2 refers to a different part of the Spi1 complex.

Data from ChIP analysis and functional variances imply that Ikzf1 has the ability to inhibit or active Spi1/ Spi1_2 via different cis elements of the PU.1 gene.

Increased Runx1 activity is associated with increased Spi1_2 activity.

Increased Cebpa activity is associated with decreased Spi1 activity.

In some cases, increased Csf1r_activated activity has been known to increase Spi1_2 activity.

It is predicted that Cebpb regulates Spi1 from ChIP-seq meta- analysis data.

Gfi1 can inhibit Spi1_2 through binding.

It is predicted that Cebpb regulates Spi1 from ChIP-seq meta- analysis data.

 S_27 1 S_9 1 S_19 1 S_17 1 S_15 1 S_27 1 S_9 1 S_23 1 S_30 1 S_5 1

E2A_protein_active activates Foxo1_gene, unless Cebpa or Cebpb is active.

Cebpa inhibtis Foxo1_gene through an unknown mechanism.

Cebpb inhibits Foxo1_gene through an unknown mechanism.

E2A_protein_active activates Foxo1_gene through binding.

 S_33 1 S_30 1 S_5 1

Spi1 activates Runx1.

Increased Spi1 activity is associated with increased Runx1 activity.

 S_9 1

E2A_gene activates E2A.

E2A refers to the activated part of the E2A_gene.

 S_1 1

Spi1 activates Mac1_gene.

Increased Spi1 activity is assoicated with increased Mac1_gene activity.

 S_9 1

Cebpa or Cebpa_gene activate Cebpa.

Cebpa is known to renew itself.

Cebpa refers to the activated from of the cebpa_gene.

 S_30 1 S_13 1

Pax5_protein_active or Spi1_2 activate Egr1.

Spi1 activates Egr1, unless Gfi1 is active.

Spi1 activates Egr1 through binding.

Spi1 activates Egr1 through binding.

Egr1 activity has been known to decrease in the presence of Gfi1.

Increased Pax5_protein_active is associated with increased Egr1 activity.

 S_24 1 S_9 1 S_19 1 S_10 1

Ebf1 and Foxo1 activate IL7r, unless Cebpa or Cebpb are active.

Spi1 and Mef2c activate IL7r, unless Cebpa or Cebpb are active.

Through interactions with a conserved ETS binding site, Spi1 activates Il7r.

Increased Cebpa activity has been known to downregulate IL7R.

Increased Cebpb activity has been known to downregulate IL7R.

Increased Ebf1 activity is associated with increased IL7r activity.

Increased Foxo1 activity is associated with increased IL7r activity.

Increased Mef2c activity is associated with increased IL7r activity.

 S_9 1 S_14 1 S_30 1 S_5 1 S_7 1 S_15 1 S_30 1 S_5 1

E2A activates E2A_protein_active, unless Id2 is active.

E2A produces E2A_protein_active.

Id2 inhibits E2A_protein_active through binding.

 S_28 1 S_3 1