Supplementary Figure 1 A

B C Prediction of top 50 Hnf4α target genes GRN inference method: CellOracle (Liver base GRN + scRNA-seq)

D Prediction of top 50 Hnf4α target genes E AUC score comparison: Prediction of top 50 Hnf4α target genes GRN inference method: GENIE3

F Supplementary Figure 2

Gata1 A MEP B

Erythroid lineage

!"#$%&'()%Sfpi/PU.1

Megakaryocytes

Gfi1

GMP

late_GMP

Cebpα

Granulocytes

Klf1

Monocytes Supplementary Figure 3 A

Provincical Hub gene Connector Hub gene Kinless Hub gene

Network module Whithin-module connection

Inter-module 2.5 connection Ultra Peripheral gene Peripheral gene Connector gene Kinless gene Whithin-module degree (z)

Network module

0.05 0.3 0.6 0.75 0.8 Participation coefficient (P) B Supplementary Figure 4

Gata1 overexpression simulation A B GMP D E Mk Mk Monocyte GMP

MEP late_GMP MEP High late_GMP

GMP C Mk

Granulocytes Low

late_GMP MEP Erythroid

F Cebpα Knockout simulation G GMP I J Mk Mk Monocyte GMP MEP late_GMP MEP High late_GMP

GMP H Mk

Granulocytes Low late_GMP MEP Erythroid

K Cebpε Knockout simulation L N O Monocyte Mk GMP Monocyte

MEP Granulocytes High late_GMP late_GMP M GMP Monocyte Granulocytes Low Granulocytes

Erythroid late_GMP GMP Supplementary Figure 5 A B Hnf4α-Foxa1

day 28

day 21

day 15

day 12

day 9

day 6

day 3

day 0

C Cdh1 Apoa1 Kng1 Col1a2

Mettl7a1 Peg3 Igf2 Fzd1

D Supplementary Figure 6

A Dead-end-destined cells B Reprogramming-destined cells

C Dead-end-destined cells

Reprogrammed-destined cells D Zeb1 *** ** ** ** ***

Fibroblasts Transition Dead-end

Early TransitionReprogrammed

E Zeb1 Knockout simulation F

Reprogrammed_iEP iEP_2 Tran_0 iEP_0 Tran_2 Early_ Transition Transition

Dead-end Dead-end_2

Fibroblasts Dead-end_0 Dead-end_1 Supplementary Figure 7 A B

C Zfp57 D E Without cell dissociation With cell dissociation

*** *** *** *** *** *** *** expression Zfp57 Scaled

Transition Fibroblasts Dead-end

Early_transition

Reprogrammed_iEP

F Zfp57 Overexpression simulation G Zfp57 Knockout simulation

Reprogrammed_iEP Reprogrammed_iEP

Transition Transition Early_ Early_ Transition Transition

Dead-end Dead-end

Fibroblasts Fibroblasts

H Hnf4α-Foxa1 Hnf4α-Foxa1-Zfp57 *

-Foxa1 -Foxa1- α α

Hnf4 Hnf4 Zfp57 Supplementary Figure 8

A Jun Junb Jund C Jun Junb Jund

*** *** *** B *** *** *** *** n.s. *** *** *** *** *** *** *** expression expression expression Jun Jund Junb Scaled Scaled Scaled

Transition Transition Transition Fibroblasts Dead-end Fibroblasts Dead-end Fibroblasts Dead-end

Early_transition Early_transition Early_transition

Reprogrammed_iEP Reprogrammed_iEP Reprogrammed_iEP

Fos gene Spliced RNA count D Without cell dissociation With cell dissociation E

** **

iEP iEP

Fibroblast Fibroblast

F Expanded iEPs Apoa1 G Fos Knockout simulation iEP_1

iEP_2 Intermediate

Fibroblast- iEP_3 like

Cdh1 Col4a1 High

Expression Low

Serpina1b Areg