Huafeng Xie , Min Ye , Ru Feng , and Thomas Graf *

Department of Developmental and Molecular Biology, Albert Einstein College of Medicine Cancer Research Center, 1300 Morris Park Avenue, Bronx, NY 10461 USA

^* Correspondence:  Thomas Graf:  (718) 430-2786 (phone),  (718) 430-3305 (fax),
E-mail:   graf@aecom.yu.edu

Starting with multipotent progenitors, hematopoietic lineages are specified by lineage-restricted transcription
factors. The transcription factors that determine the decision between lymphoid and myeloid cell fates, and the underlying mechanisms, remain largely unknown. Here, we report that enforced expression of C/EBPa and C/EBPb in differentiated B cells leads to their rapid and efficient reprogramming into macrophages. C/EBPs induce these changes by inhibiting the B cell commitment transcription factor Pax5, leading to the
downregulation of its target CD19, and synergizing with endogenous PU.1, an ETS family factor, leading to the
upregulation of its target Mac-1 and other myeloid markers. The two processes can be uncoupled, since, in
PU.1-deficient pre-B cells, C/EBPs induce CD19 downregulation but not Mac-1 activation. Our observations
indicate that C/EBPa and b remodel the transcription network of B cells into that of macrophages through a
series of parallel and sequential changes that require endogenous PU.1.

Figure 7. Summary of the Observed B Cell to Macrophage Conversion

(A) Changes occurring at the cell surface after infection of a CD19-expressing B cell with a C/EBP virus. The cell is shown to turn into Mac-1+ after passing through an intermediate that expresses low levels of CD19 and Mac-1 antigen. CD19, red circles; Mac-1, green squares.

(B) Changes occurring inside the nucleus. Straight arrows and T-shaped bars indicate activation and inhibition, respectively. Curved arrow, autoregulation; open arrows, up- or downregulation. Dashed lines indicate uncertainty.

1. Frenster JH, and Hovsepian JA, "Activator RNA Exchange during Interphase Chromatin Reprogramming".

2. Prasanth KV, Sacco-Bubulya PA, Prasanth SG, and Spector DL, "Sequential Entry of Components of Gene Expression Machinery into Daughter Nuclei", Mol. Biol. Cell, 14: 1043 (2003).

3. Frenster JH, and Hovsepian JA,  "Overshoot in Late Telophase for RNA Re-Programming of Mitotic Chromatin",  RNA 2003, 211 (2003).

4. Frenster JH, "Yeast  RNA  Re-Programming  of  Already-Active  Mammalian Chromatin".  RNA 2002, 592 (2002).

5. Frenster JH, "Activation of DNA Transcription within Repressed Chromatin by Nuclear RNA Species",    RNA 2001, 237 (2001).

6. Hovsepian JA, and Frenster JH, "RNA-Induced Melting of DNA during Selective Gene Transcription",
Molec. Biol. Cell, vol. 13, supp. p. 239a (November, 2002).

7. Kuwabara T, Hsieh J, Nakashima K, Taira K, and Gage FH, "A Small Modulatory dsRNA Specifies the Fate of Adult Neural Stem Cells". Cell,  vol. 116, no. 6, pp.779-793  (19 March 2004).
 

Additional References on Reprogramming of Chromatin:

1. Byrne JA, Simonsson S, Western PS, and Gurdon JB, "Nuclei of Adult Mammalian Somatic Cells are Directly Reprogrammed to oct-4 Stem Cell Gene Expression by Amphibian Oocytes", Current Biology, vol 13, no. 14, pp. 1206-1213 (July 15, 2003).

2. Li L, Connelly MC, Wetmore C, Curran T, and Morgan JI, "Mouse Embryos Cloned from Brain Tumors", Cancer Research vol. 63, no. 11, pp. 2733-2736 (June 1, 2003).

3. Goldstein L, “Stable Nuclear RNA Returns to Post-Division Nuclei Following Release to Cytoplasm during Mitosis”, Exp. Cell Res. vol. 89,  no. 2, pp. 421-425 (December, 1974).

4. Geiss G, Jin G, Guo J, Bumgarner R, Katze MG, and Sen GC, "A Comprehensive View of Regulation of Gene Expression by Double-Stranded RNA-Mediated Cell Signaling", J. Biol. Chem. vol. 276, pp. 30178-30182 (2001).

5. Persengiev SP, Zhu X and Green MR, "Nonspecific, concentration-dependent stimulation and repression of mammalian gene expression by small interfering RNAs (siRNAs)",  RNA, vol. 10, no. 1, pp. 12-18 (January, 2004).

6. Gottesfeld JM,  and Barbas III CF, "RNA as a Transcriptional Activator", Chemistry and Biology, vol 10, no.7, pp. 584-585 (July, 2003).

Links to Euchromatin Activator RNA Reviews:
Links to Euchromatin Activator RNA Research:
Links to Ultrastructural Probes of DNase I-Sensitive Sites:
Links to RNA as a Therapeutic Agent:
Links to Hodgkin Lymphoma Immuno-Pathology:
Links to Activated T-Lymphocyte Immunotherapy:
Links to Medical Systems Biology:

"Ultrastructural Probes of Active DNA Sites, and the RNA Activators of DNA".

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